Org 214007-0: a novel non-steroidal selective glucocorticoid receptor modulator with full anti-inflammatory properties and improved therapeutic index

Contains fulltext : 103595.pdf (publisher's version ) (Open Access)Glucocorticoids (GCs) such as prednisolone are potent immunosuppressive drugs but suffer from severe adverse effects, including the induction of insulin resistance. Therefore, development of so-called Selective Glucocorticoid Receptor Modulators (SGRM) is highly desirable. Here we describe a non-steroidal Glucocorticoid Receptor (GR)-selective compound (Org 214007-0) with a binding affinity to GR similar to that of prednisolone. Structural modelling of the GR-Org 214007-0 binding site shows disturbance of the loop between helix 11 and helix 12 of GR, confirmed by partial recruitment of the TIF2-3 peptide. Using various cell lines and primary human cells, we show here that Org 214007-0 acts as a partial GC agonist, since it repressed inflammatory genes and was less effective in induction of metabolic genes. More importantly, in vivo studies in mice indicated that Org 214007-0 retained full efficacy in acute inflammation models as well as in a chronic collagen-induced arthritis (CIA) model. Gene expression profiling of muscle tissue derived from arthritic mice showed a partial activity of Org 214007-0 at an equi-efficacious dosage of prednisolone, with an increased ratio in repression versus induction of genes. Finally, in mice Org 214007-0 did not induce elevated fasting glucose nor the shift in glucose/glycogen balance in the liver seen with an equi-efficacious dose of prednisolone. All together, our data demonstrate that Org 214007-0 is a novel SGRMs with an improved therapeutic index compared to prednisolone. This class of SGRMs can contribute to effective anti-inflammatory therapy with a lower risk for metabolic side effects

Mycobacterium avium Pleuritis in a Non-Immunocompromised Patient

Nontuberculous mycobacterium infection is rarely accompanied by pleural involvement. We describe a very rare occurrence of Mycobacterium (M) avium pleuritis with pleural effusion in a non-compromised 73-year-old woman patient who had been treated for sick sinus syndrome. She was admitted to our hospital with general malaise and left pleural effusion. To establish a definitive diagnosis, a biopsy specimen was obtained from the left parietal pleura by video-assisted thoracoscopic surgery. The pleural biopsy specimen revealed only diffuse lymphoid cell infiltration and neoplastic or granulomatous lesions were absent. Culture of the pleural biopsy specimen revealed M. avium, indicating that the pleuritis was caused by this organism. A course of anti-tubercular agents (rifampin, ethambutol and streptomycin sulfate) and clarithromycin gradually resolved the pleural effusion