An anti-TNF-glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases.

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti-tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti-TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti-TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti-TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti-TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.

Ginsenoside Compound K Reduces Psoriasis-related Inflammation by Activation of the Glucocorticoid Receptor in Keratinocytes.

AIM: To investigate the effects and mechanism of Ginsenoside Compound K (GCK) on psoriasis, focusing on the glucocorticoid receptor (GR) in keratinocytes. METHODS: An imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model was generated to evaluate the anti-inflammatory effect of GCK. Hematoxylin and eosin (H&E) staining was used to assess skin pathological changes. Protein expression of K17 and p-p65 in mice skin was assayed by immunohistochemical. Protein expression and phosphorylation of p65 IκB were assayed by Western blot. Protein expression of K1, K6, K10, K16, K17, and GR were assayed by Western blot and immunofluorescence. Enzyme-linked immunosorbent assay (ELISA) was used to determine cytokine levels of TNF-α, IL-6, CXCL-8, and ICAM-1. Real-time polymerase chain reaction (RT-PCR) was used to quantify TNF-α, IL-6, IL-8, and ICAM-1 mRNA expression. Cell viability was determined by Cell Counting Kit-8(CCK-8) assay. A high-content cell-imaging system was used to assay cell proliferation. Nuclear translocation of p65 and GR was assayed by imaging flow cytometry and immunofluorescence microscopy. Small interfering RNA was used to confirm the role of GR in the anti-inflammatory and immunoregulatory effect of GCK in normal human epidermal keratinecytes (NHEKs). RESULTS: GCK reduced the psoriasis area, severity index, and epidermal thickening in IMQ-induced mice. GCK significantly attenuated the mRNA levels of IL-6, IL-8, TNF-α, and ICAM-1 and reduced epidermal hyperproliferation in the skin of IMQ-induced mice. GCK inhibited in vitro activation of NF-κB, leading to attenuated release of inflammatory mediators (IL-6, IL-8, TNF-α, and ICAM-1) and suppression of NHEK hyperproliferation and abnormal differentiation. These inhibitory effects of GCK were diminished by GR silencing in NHEKs. CONCLUSION: GCK suppressed psoriasis-related inflammation by suppressing keratinocyte activation, which may be related to promoting GR nuclear translocation and inhibiting NF-κB activation. In summary, GCK appears to be a GR activator and a promising therapeutic candidate for antipsoriatic agents.

Identification of FDA-approved drugs that increase mevalonate kinase in hyper IgD syndrome.

Mevalonate kinase deficiency (MKD) is an autoinflammatory metabolic disorder caused by bi-allelic loss-of-function variants in the MVK gene, resulting in decreased activity of the encoded mevalonate kinase (MK). Clinical presentation ranges from the severe early-lethal mevalonic aciduria to the milder hyper-IgD syndrome (MKD-HIDS), and is in the majority of patients associated with recurrent inflammatory episodes with often unclear cause. Previous studies with MKD-HIDS patient cells indicated that increased temperature, as caused by fever during an inflammatory episode, lowers the residual MK activity, which causes a temporary shortage of non-sterol isoprenoids that promotes the further development of inflammation. Because an increase of the residual MK activity is expected to make MKD-HIDS patients less sensitive to developing inflammatory episodes, we established a cell-based screen that can be used to identify compounds and/or therapeutic targets that promote this increase. Using a reporter HeLa cell line that stably expresses the most common MKD-HIDS variant, MK-V377I, C-terminally tagged with bioluminescent NanoLuc luciferase (nLuc), we screened the Prestwick Chemical Library®, which includes 1280 FDA-approved compounds. Multiple compounds increased MK-V377I-nLuc bioluminescence, including steroids (i.e., glucocorticoids, estrogens, and progestogens), statins and antineoplastic drugs. The glucocorticoids increased MK-V377I-nLuc bioluminescence through glucocorticoid receptor signaling. Subsequent studies in MKD-HIDS patient cells showed that the potent glucocorticoid clobetasol propionate increases gene transcription of MVK and other genes regulated by the transcription factor sterol regulatory element-binding protein 2 (SREBP-2). Our results suggest that increasing the flux through the isoprenoid biosynthesis pathway by targeting the glucocorticoid receptor or SREBP-2 could be a potential therapeutic strategy in MKD-HIDS.

Genetically engineered human pituitary corticotroph tumor organoids exhibit divergent responses to glucocorticoid receptor modulators.

Cushing's disease (CD) is a serious endocrine disorder attributed to an adrenocorticotropic hormone (ACTH)-secreting pituitary neuroendocrine tumor (PitNET) that that subsequently leads to chronic hypercortisolemia. PitNET regression has been reported following treatment with the investigational selective glucocorticoid receptor (GR) modulator relacorilant, but the mechanisms behind that effect remain unknown. Human PitNET organoid models were generated from induced human pluripotent stem cells (iPSCs) or fresh tissue obtained from CD patient PitNETs (hPITOs). Genetically engineered iPSC derived organoids were used to model the development of corticotroph PitNETs expressing USP48 (iPSCUSP48) or USP8 (iPSCUSP8) somatic mutations. Organoids were treated with the GR antagonist mifepristone or the GR modulator relacorilant with or without somatostatin receptor (SSTR) agonists pasireotide or octreotide. In iPSCUSP48 and iPSCUSP8 cultures, mifepristone induced a predominant expression of SSTR2 with a concomitant increase in ACTH secretion and tumor cell proliferation. Relacorilant predominantly induced SSTR5 expression and tumor cell apoptosis with minimal ACTH induction. Hedgehog signaling mediated the induction of SSTR2 and SSTR5 in response to mifepristone and relacorilant. Relacorilant sensitized PitNET organoid responsiveness to pasireotide. Therefore, our study identified the potential therapeutic use of relacorilant in combination with somatostatin analogs and demonstrated the advantages of relacorilant over mifepristone, supporting its further development for use in the treatment of Cushing's disease patients.

Características clínicas, tratamiento y evolución de una serie de niños con síndrome inflamatorio multisistémico asociado a SARS-CoV-2 hospitalizados en dos centros de salud / Clinical characteristics, treatment and evolution of a series of children with multisystemic inflammatory syndrome associated with SARS-CoV-2 hospitalized in two health centers / Características clínicas, tratamento e evolução de uma série de crianças com síndrome inflamatória multissistêmica associada ao SARS-CoV-2 internadas em dois centros de saúde

Introducción: en marzo del 2021 se registró el pico de incidencia de COVID-19 en Uruguay y un aumento de la infección en pediatría. Objetivo: describir las características clínicas, el tratamiento y la evolución de una serie de menores de 15 años con SIM-Ped S hospitalizados en dos centros de salud. Metodología: estudio descriptivo, retrospectivo, de los niños hospitalizados entre el 1/3 y el 31/6 de 2021 que cumplieron los criterios diagnósticos de SIM-Ped de la OMS. Se analizan variables clínicas, paraclínicas, tratamiento y evolución. Resultados: se incluyeron 12 niños, mediana de edad 7 años (22 meses-10 años). Se presentaron complicación posinfecciosas en 8 y en el curso de la infección en 4. Las manifestaciones fueron: fiebre (media 6 días, rango 3-10), digestivas 10 y mucocutáneas 7. Se presentaron como enfermedad Kawasaki símil 5 y como shock 2. La infección por SARS CoV-2 se confirmó por PCR en 6, serología 4 y test antigénico 2. Recibieron tratamiento en cuidados moderados 8 e intensivos 4: inmunoglobulina 9, corticoides 11, heparina 7 y ácido acetilsalicílico 7. Presentaron dilatación de arterias coronarias 2, alteraciones valvulares 2, disminución de la FEVI 2 y derrame pericárdico 2. Todos evolucionaron favorablemente. Conclusiones: en estos centros, los primeros casos de SIMS-Ped S coincidieron con el pico de incidencia de COVID-19 en el país. Predominaron las formas postinfecciosas en escolares con manifestaciones digestivas. Este estudio puede contribuir al reconocimiento de esta entidad y adecuar los algoritmos nacionales de manejo.

Introduction: in March 2021, there was a peak incidence of COVID-19 and an increase in pediatric infections in Uruguay. Objective: describe the clinical characteristics, treatment and evolution of a group of children under 15 years of age with SIM-Ped S hospitalized in two health centers. Methodology: descriptive, retrospective study of children hospitalized between 3/1 and 6/31 of 2021 who met the WHO diagnostic criteria for SIM-Ped. Clinical and paraclinical variables, as well as treatment and evolution were analyzed. Results: 12 children were included, median age 7 years (22 months-10 years). Eight of them showed post-infectious complications and 4 of them had complications during the course of the infection. The manifestations were: fever (mean 6 days, range 3-10), digestive symptoms 10 and mucocutaneous 7. Five of them presented a Kawasaki-like disease and 2 of them shock. SARS CoV-2 infection was confirmed by PCR in 6 cases, serology in 4 and antigenic test in 2. Eight of them received treatment in moderate care and 4 of them in intensive care: immunoglobulin 9, corticosteroids 11, heparin 7 and acetylsalicylic acid 7. Two of them presented dilated arteries coronary , valvular alterations 2, decreased LVEF 2 and pericardial effusion 2. All progressed favorably. Conclusions: in these centers, the first cases of SIMS-Ped S coincided with the peak incidence of COVID-19 in the country. Post-infectious forms predominated in schoolchildren who showed digestive manifestations. This study may contribute to the recognition of this entity and to the adaptation of national management algorithms.

Introdução: em março de 2021, foi registrado no Uruguai um pico de incidência da COVID-19 e um aumento dos casos da infecção pediátrica. Objetivo: descrever as características clínicas, tratamento e evolução de uma série de crianças menores de 15 anos com SIM-Ped S internadas em dois centros de saúde. Metodologia: estudo descritivo, retrospectivo, de crianças internadas entre 1/3 e 31/6 de 2021 que preencheram os critérios diagnósticos da OMS para o SIM-Ped. Foram analisadas variáveis clínicas e para-clinicas, tratamento e evolução. Resultados: foram incluídas 12 crianças, com idade média de 7 anos (22 meses-10 anos). Oito delas apresentaram complicações pós-infecciosas e 4 delas durante o curso da infecção. As manifestações foram: febre (média de 6 dias, intervalo 3-10), digestivas 10 e mucocutânea 7. Cinco delas apresentaram doença de Kawasaki-like e 2 delas sofreram Shock. A infecção por SARS CoV-2 foi confirmada por PCR em 6, sorologia em 4 e teste antigênico em 2. Oito delas receberam tratamento em cuidados moderados e 4 delas em cuidados intensivos: imunoglobulina 9, corticosteroides 11, heparina 7 e ácido acetilsalicílico 7. Duas delas apresentaram artérias coronárias dilatadas 2, alterações valvares 2, diminuição da FEVE 2 e derrame pericárdico 2. Todas evoluíram favoravelmente. Conclusões: nesses centros, os primeiros casos de SIMS-Ped S coincidiram com um pico de incidência de COVID-19 no país. As formas pós-infecciosas predominaram em escolares com manifestações digestivas. Este estudo pode contribuir para o reconhecimento desta entidade e adaptar algoritmos nacionais de gestão.

Glucocorticoid receptor blockers.

Mifepristone is the only glucocorticoid receptor antagonist currently approved for the treatment of Cushing's syndrome. Although originally developed as an abortifacient due to its blockade of the progesterone receptor, a number of case reports documented its efficacy as a glucocorticoid receptor blocker going back to 1985. The SEISMIC trial, published in 2012, provided sufficient data on efficacy and adverse effects for regulatory approval. Mifepristone provides clear benefits on glycemia, blood pressure, muscle weakness, body weight and the other myriad clinical manifestations of Cushing's syndrome. However, because it blocks the glucocorticoid receptor, blood cortisol and ACTH levels actually rise, rather than fall; this complicates patient management. Doses are adjusted based on clinical manifestations rather than hormone levels. Adverse effects include adrenal insufficiency due to overdosage, hypokalemia, and menorrhagia. Treatment of severe adrenal insufficiency requires high doses of dexamethasone. Other glucocorticoid receptor blockers without effects on the progesterone receptor are being developed. Because mifepristone inhibits CYP3A and CYP2C8/2C9, drug-drug interactions can occur. These potential adverse effects can largely be avoided with careful attention to detail. My opinion is that its current place in therapy is in patients with severe disease and in those not responding to other treatments.

Ipriflavone as a non-steroidal glucocorticoid receptor antagonist ameliorates diabetic cognitive impairment in mice.

Diabetic cognitive impairment (DCI) is a common diabetic complication with hallmarks of loss of learning ability and disorders of memory and behavior. Glucocorticoid receptor (GR) dysfunction is a main reason for neuronal impairment in brain of diabetic patients. Here, we determined that ipriflavone (IP) a clinical anti-osteoporosis drug functioned as a non-steroidal GR antagonist and efficiently ameliorated learning and memory dysfunction in both type 1 and 2 diabetic mice. The underlying mechanism has been intensively investigated by assay against the diabetic mice with GR-specific knockdown in the brain by injection of adeno-associated virus (AAV)-ePHP-si-GR. IP suppressed tau hyperphosphorylation through GR/PI3K/AKT/GSK3ß pathway, alleviated neuronal inflammation through GR/NF-κB/NLRP3/ASC/Caspase-1 pathway, and protected against synaptic impairment through GR/CREB/BDNF pathway. To our knowledge, our work might be the first to expound the detailed mechanism underlying the amelioration of non-steroidal GR antagonist on DCI-like pathology in mice and report the potential of IP in treatment of DCI.

[Expression of glucocorticoid receptor in prostate cancer and its clinical significance].

OBJECTIVE: To investigate the expression of glucocorticoid receptor (GR) in the PCa tissue and its correlation with the clinicopathological characteristics and prognosis of PCa. METHODS: Using immunohistochemical staining, we determined the expression of GR in the PCa tissue and analyzed its correlation with the clininicopathological features and prognosis of the malignancy. RESULTS: The positive expression of GR in the PCa tissue was 64%, of which the strongly positive rate was 34.7%. The GR expression was positively correlated with preoperative androgen-deprivation therapy (ADT) (χ2 = 22.307, P < 0.01), Gleason grades (χ2 = 16.534, P = 0.002) and clinical stages of the tumor (χ2 = 9.969, P = 0.041). Kaplan-Meier analysis showed that the GR expression was correlated not with the overall survival (P = 0.156), but with the PSA progression-free survival rate of the PCa patients (P = 0.042), with a shorter PSA progression-free survival time in those with a higher GR expression. Multivariate COX regression analysis revealed that the expression of GR was not an independent prognostic factor for PSA progression-free survival of the PCa patients. CONCLUSION: The expression of GR is related with preoperative ADT, and closely with the biological behavior of the malignancy and treatment resistance of the patients. GR is expected to be a new effective therapeutic target and a prognostic biomarker for PCa.

Intestinal epithelial glucocorticoid receptor promotes chronic inflammation-associated colorectal cancer.

Synthetic immunosuppressive glucocorticoids (GCs) are widely used to control inflammatory bowel disease (IBD). However, the impact of GC signaling on intestinal tumorigenesis remains controversial. Here, we report that intestinal epithelial GC receptor (GR), but not whole intestinal tissue GR, promoted chronic intestinal inflammation-associated colorectal cancer in both humans and mice. In patients with colorectal cancer, GR was enriched in intestinal epithelial cells and high epithelial cell GR levels were associated with poor prognosis. Consistently, intestinal epithelium-specific deletion of GR (GR iKO) in mice increased macrophage infiltration, improved tissue recovery, and enhanced antitumor response in a chronic inflammation-associated colorectal cancer model. Consequently, GR iKO mice developed fewer and less advanced tumors than control mice. Furthermore, oral GC administration in the early phase of tissue injury delayed recovery and accelerated the formation of aggressive colorectal cancers. Our study reveals that intestinal epithelial GR signaling repressed acute colitis but promoted chronic inflammation-associated colorectal cancer. Our study suggests that colorectal epithelial GR could serve as a predictive marker for colorectal cancer risk and prognosis. Our findings further suggest that, although synthetic GC treatment for IBD should be used with caution, there is a therapeutic window for GC therapy during colorectal cancer development in immunocompetent patients.

GLCCI1 gene body methylation in peripheral blood is associated with asthma and asthma severity.

BACKGROUND AND AIMS: Epigenetic changes play a role in the occurrence of asthma. In this study, we evaluated the methylation status of glucocorticoid-induced transcript 1 (GLCCI1) and assessed its associations with asthma and asthma severity. MATERIALS AND METHODS: Peripheral blood mononuclear cells were harvested from 33 severe asthma patients, 84 mild-moderate asthma patients and 79 healthy controls of Han nationality. GLCCI1 methylation were screened using the MassArray Epityper platform (Agena). We also conducted mRNA sequencing of GLCCI1-knockout mice to further explore possible functions of this gene. RESULTS: We found 5 GLCCI1 methylation sites independently correlated with asthma (adjusted p < 0.05) and perform well in asthma prediction with optimum area under the curve (AUC) value was 0.846 (p < 0.0001). In asthmatic group, only one sites independently associates with severe asthma. Area under the curve in predicting severe asthma is comparable with forced expiratory volume in 1 s predicted (AUC 0.865 and 0.857, p = 0.291). Spearman correlate analysis denoted GLCCI1 low methylation is associates with its low expression in asthma PBMCs. Its reduced level may influence PI3k-Akt and MAPK pathways by the results of RNA sequencing of GLCCI1-knockout mice (adjusted p value < 0.01). CONCLUSIONS: Our research indicates a low GLCCI1 methylation level in asthma with certain sites are lower in severe asthma group. These GLCCI1 methylation sites may be contributed to detect asthma and asthma severity.

A follow-up history of young man with apparent cortisone reductase deficiency (ACRD) - several years after diagnosis.

INTRODUCTION: Inactivating mutations in the enzyme hexose-6-phosphate dehydrogenase (H6PDH), the enzyme responsible for NADPH generation playing critical role in 11-hydroxysteroid dehydrogenase type 1 (11b-HSD1) activity, cause apparent cortisone reductase deficiency (ACRD). It leads to increased metabolic clearance rate of cortisol due to a defect in cortisone to cortisol conversion by 11b-HSD1. We want to analyse the process of the disease, efficacy of long-lasting treatment with glucocorticoids throughout childhood and adolescence in only male patient with ACRD. CASE PRESENTATION: A 23 year-old male patient was diagnosed with ACRD at the age of 7 years. The clinical manifestation of ACRD was presented by precocious pubarche. His bone age was assessed as 11.5 years old. Blood tests indicated increased the plasma androgen, with elevated 17-hydroxyprogesterone concentration. A steroid profile analysis of a 24-h urine collection showed extremely reduced THF + allo-THF/THE ratio - 0.021 (normal range: 0.7-1.2). Two months of hydrocortisone therapy was ineffective and dexamethasone was administered in initial dose of 0.375 mg/24 h. Next dosage beetwen 0.125 mg/24h and 0.375 mg/24h has been changed depending on the patient's results of laboratory tests and condition. Control laboratory studies indicated suppression of excess adrenal androgen synthesis, but we never got the THF + allo-THF/THE ratio in normal values. He did not develop any serious side effects, although dexamethasone is the most potent adrenal suppression drug. CONCLUSIONS: Hydrocortisone treatment is ineffective in ACRD patients because it was rapidly metabolized to cortisone. We have found the balance between the dexamethasone treatment effects of adrenal suppression and the achievement of full height potential considering the condition of our patient.

Effects of Ketoconazole on the Pharmacokinetics of Mifepristone, a Competitive Glucocorticoid Receptor Antagonist, in Healthy Men.

INTRODUCTION: Mifepristone, a competitive glucocorticoid receptor antagonist approved for Cushing syndrome, and ketoconazole, an antifungal and steroidogenesis inhibitor, are both inhibitors of and substrates for cytochrome P450 (CYP3A4). This study evaluated the pharmacokinetic effects of concomitant ketoconazole, a strong CYP3A4 inhibitor, on mifepristone. METHODS: In an open-label, two-period, single-center study, healthy adult men received mifepristone 600 mg orally daily for 12 days (period 1) followed by mifepristone 600 mg daily plus ketoconazole 200 mg orally twice daily for 5 days (period 2). Serial pharmacokinetic blood samples were collected predose and over 24 h postdose on days 12 (period 1) and 17 (period 2). A cross-study comparison (using data on file) further examined whether systemic exposure to mifepristone plus ketoconazole exceeded the exposure following mifepristone 1200 mg orally administered for 7 days. RESULTS: Sixteen subjects were enrolled and 14 completed the study. Concomitant administration with ketoconazole increased the systemic exposure to mifepristone, based on geometric least squares mean ratios, by 28% for C max and 38% for AUC0-24. This increase was 85% and 87% of the exposure observed following mifepristone's highest label dose of 1200 mg/day for C max and AUC0-24, respectively. Adverse events (AEs) were reported in 56.3% (9/16) of subjects during administration of mifepristone alone and in 57.1% (8/14) during combination with ketoconazole. No serious AEs were reported. CONCLUSION: Systemic exposure to mifepristone increased following multiple doses of mifepristone 600 mg daily plus ketoconazole 200 mg twice daily. Little to no increase in AEs occurred. Dose adjustment of mifepristone may be needed when given with ketoconazole. FUNDING: Corcept Therapeutics.

Six-minute walk test and respiratory muscle strength in patients with uncontrolled severe asthma: a pilot study.

OBJECTIVE: To evaluate respiratory muscle strength and six-minute walk test (6MWT) variables in patients with uncontrolled severe asthma (UCSA). METHODS: This was a cross-sectional study involving UCSA patients followed at a university hospital. The patients underwent 6MWT, spirometry, and measurements of respiratory muscle strength, as well as completing the Asthma Control Test (ACT). The Mann-Whitney test was used in order to analyze 6MWT variables, whereas the Kruskal-Wallis test was used to determine whether there was an association between the use of oral corticosteroids and respiratory muscle strength. RESULTS: We included 25 patients. Mean FEV1 was 58.8 ± 21.8% of predicted, and mean ACT score was 14.0 ± 3.9 points. No significant difference was found between the median six-minute walk distance recorded for the UCSA patients and that predicted for healthy Brazilians (512 m and 534 m, respectively; p = 0.14). During the 6MWT, there was no significant drop in SpO2. Mean MIP and MEP were normal (72.9 ± 15.2% and 67.6 ± 22.2%, respectively). Comparing the patients treated with at least four courses of oral corticosteroids per year and those treated with three or fewer, we found no significant differences in MIP (p = 0.15) or MEP (p = 0.45). CONCLUSIONS: Our findings suggest that UCSA patients are similar to normal subjects in terms of 6MWT variables and respiratory muscle strength. The use of oral corticosteroids has no apparent impact on respiratory muscle strength.

Six-minute walk test and respiratory muscle strength in patients with uncontrolled severe asthma: a pilot study / Teste de caminhada de seis minutos e força muscular respiratória em pacientes com asma grave não controlada: um estudo piloto

OBJECTIVE: To evaluate respiratory muscle strength and six-minute walk test (6MWT) variables in patients with uncontrolled severe asthma (UCSA). METHODS: This was a cross-sectional study involving UCSA patients followed at a university hospital. The patients underwent 6MWT, spirometry, and measurements of respiratory muscle strength, as well as completing the Asthma Control Test (ACT). The Mann-Whitney test was used in order to analyze 6MWT variables, whereas the Kruskal-Wallis test was used to determine whether there was an association between the use of oral corticosteroids and respiratory muscle strength. RESULTS: We included 25 patients. Mean FEV1 was 58.8 ± 21.8% of predicted, and mean ACT score was 14.0 ± 3.9 points. No significant difference was found between the median six-minute walk distance recorded for the UCSA patients and that predicted for healthy Brazilians (512 m and 534 m, respectively; p = 0.14). During the 6MWT, there was no significant drop in SpO2. Mean MIP and MEP were normal (72.9 ± 15.2% and 67.6 ± 22.2%, respectively). Comparing the patients treated with at least four courses of oral corticosteroids per year and those treated with three or fewer, we found no significant differences in MIP (p = 0.15) or MEP (p = 0.45). CONCLUSIONS: Our findings suggest that UCSA patients are similar to normal subjects in terms of 6MWT variables and respiratory muscle strength. The use of oral corticosteroids has no apparent impact on respiratory muscle strength. .

OBJETIVO: Avaliar a força muscular respiratória e variáveis obtidas no teste de caminhada de seis minutos (TC6) em pacientes com asma grave não controlada (AGNC). MÉTODOS: Estudo transversal, envolvendo pacientes com AGNC acompanhados em um hospital universitário. Os pacientes foram submetidos a TC6, espirometria e medidas da força muscular respiratória e responderam o Asthma Control Test (ACT, Teste de Controle da Asma). O teste de Mann-Whitney foi utilizado na análise das variáveis do TC6, e o teste de Kruskal-Wallis foi utilizado na verificação de uma possível associação do uso de corticoide oral com a força muscular respiratória. RESULTADOS: Foram incluídos 25 pacientes, com médias de VEF1 de 58,8 ± 21,8% do previsto e escore do ACT de 14,0 ± 3,9 pontos. Não houve diferença significativa entre a mediana da distância percorrida no TC6 dos pacientes com AGNC e aquela prevista para brasileiros saudáveis (512 m e 534 m, respectivamente; p = 0,14). Durante o TC6, não houve queda significativa da SpO2. As médias de PImáx e PEmáx foram normais (72,9 ± 15,2% e 67,6 ± 22,2%, respectivamente). Não houve diferenças significativas nas medidas de PImáx (p = 0,15) e PEmáx (p = 0,45) entre os pacientes que usavam ao menos quatro ciclos de corticoide oral por ano e os que o usavam por três ou menos ciclos por ano. CONCLUSÕES: Nossos achados sugerem que os pacientes com AGNC são semelhantes a indivíduos normais em termos das variáveis do TC6 e da força muscular respiratória. Não se observou um impacto do uso de corticoide oral na força muscular respiratória. .

A nonsteroidal glucocorticoid receptor agonist inhibits allergen-induced late asthmatic responses.

RATIONALE: Effective antiinflammatory therapies are needed for the treatment of asthma, but preferably without the systemic adverse effects of glucocorticosteroids. OBJECTIVES: We evaluated the effect of an inhaled nonsteroidal glucocorticoid receptor agonist, AZD5423, on allergen-induced responses. METHODS: Twenty subjects with mild allergic asthma were randomized to receive 7 days of treatment with nebulized AZD5423 (75 or 300 µg) once daily, budesonide 200 µg twice daily via Turbuhaler, or placebo in a double-blind, four-period, crossover design study. Allergen challenge was performed on Day 6. MEASUREMENTS AND MAIN RESULTS: FEV1 was measured repeatedly for 7 hours after allergen challenge for early and late asthmatic responses. Sputum inflammatory cells was measured before and at 7 and 24 hours after allergen challenge, and methacholine airway responsiveness was measured before and 24 hours after allergen challenge. AZD5423 significantly attenuated the fall in FEV1 during the late asthmatic response (both doses led to an 8.7% fall) versus placebo (14% fall) (P < 0.05) with no effect of budesonide (12.5% fall) versus placebo (P > 0.05). There was no effect on the fall in FEV1 during early asthmatic response. AZD5423 300 and 75 µg significantly attenuated allergen-induced sputum eosinophilia by 63 and 61% at 7 hours, respectively, and by 46 and 34% at 24 hours after allergen challenge, respectively, versus placebo (all P < 0.05). Budesonide did not reduce allergen-induced sputum eosinophilia versus placebo. AZD5423 at 300 µg significantly attenuated allergen-induced airway hyperresponsiveness at 24 hours after allergen challenge versus placebo (P < 0.05). Both doses of AZD5423 were well tolerated. CONCLUSIONS: Seven-day treatment with inhalation of the nonsteroidal glucocorticoid receptor agonist AZD5423 effectively reduced allergen-induced responses in subjects with mild allergic asthma. Clinical trial registered with www.clinicaltrials.gov (NCT01225549).

Enhancing cognition after stress with gene therapy.

Hippocampal function is essential for the acquisition, consolidation, and retrieval of spatial memory. High circulating levels of glucocorticoids (GCs), the adrenal steroid hormones secreted during stress, have been shown to impair both acquisition and retrieval and can either impair or enhance consolidation, depending on experimental conditions. In contrast, estrogen can enhance spatial memory performance and can block the deleterious effects of GCs on such performance. We therefore constructed a chimeric gene ("ER/GR") containing the hormone-binding domain of the GC receptor and the DNA binding domain of the estrogen receptor; as a result, ER/GR transduces deleterious GC signals into beneficial estrogenic ones. We show here that acute immobilization stress, before acquisition and retrieval phases, increases latencies for male rats in a hidden platform version of the Morris water maze. This impairment is blocked by hippocampal expression of the ER/GR transgene. ER/GR expression also blocks decreases in platform crossings caused by acute stress, either after acquisition or before retrieval. Three days of stress before acquisition produces an estrogen-like enhancement of performance in ER/GR-treated rats. Moreover, ER/GR blocks the suppressive effects of GCs on expression of brain-derived neurotrophic factor (BDNF), a growth factor central to hippocampal-dependent cognition and plasticity, instead producing an estrogenic increase in BDNF expression. Thus, ER/GR expression enhances spatial memory performance and blocks the impairing effects of GCs on such performance.

Dissociated glucocorticoid receptor ligands: compounds with an improved therapeutic index.

Glucocorticoids are well known for their potent anti-inflammatory and immunosuppressive actions. However, due to their potential to induce serious undesired effects, there is a great need for compounds with a better therapeutic index. Recent discoveries have demonstrated that the positive and negative regulation of gene expression via the glucocorticoid receptor is mediated by different mechanisms. This regulation is predominantly responsible for either anti-inflammatory effects or certain side effects, depending on whether it is negative or positive. Compounds that preferentially induce transrepression rather than transactivation should be superior to classical glucocorticoids. Indeed, proof of concept has been recently achieved with such selective glucocorticoid receptor agonists.

Asthma pathophysiology and the scientific rationale for combination therapy.

The clinical and scientific description of asthma has been undergoing an evolution of continuous revision during the past 10 years. This disorder has been recognized as a complex entity with interplay between genetic, environmental, and allergenic factors resulting in a significant component of inflammation of the airway. Recent directions in therapy differ in taking either the broad-based antagonist or the specific mediator antagonist approach. This review highlights some of the scientific evidence of the operative pathophysiological events and reviews their applicability to the rationale for broad-based combination asthma therapy.