Potent Anti-Inflammatory, Arylpyrazole-Based Glucocorticoid Receptor Agonists That Do Not Impair Insulin Secretion.

Glucocorticoids (GCs) are widely used in medicine for their role in the treatment of autoimmune-mediated conditions, certain cancers, and organ transplantation. The transcriptional activities GCs elicit include transrepression, postulated to be responsible for the anti-inflammatory activity, and transactivation, proposed to underlie the undesirable side effects associated with long-term use. A GC analogue that could elicit only transrepression and beneficial transactivation properties would be of great medicinal value and is highly sought after. In this study, a series of 1-(4-substituted phenyl)pyrazole-based GC analogues were synthesized, biologically screened, and evaluated for SARs leading to the desired activity. Activity observed in compounds bearing an electron deficient arylpyrazole moiety showed promise toward a dissociated steroid, displaying transrepression while having limited transactivation activity. In addition, compounds 11aa and 11ab were found to have anti-inflammatory efficacy comparable to that of dexamethasone at 10 nM, with minimal transactivation activity and no reduction of insulin secretion in cultured rat 832/13 beta cells.

Adult Versus Pediatric Relapse and Recurrence in Orbital Inflammatory Syndrome.

PURPOSE: Orbital inflammatory syndrome (OIS) is a diagnosis of exclusion that has a variable presentation and unpredictable course. Many studies report incomplete or lack of OIS resolution with high recurrence and relapse rates. No studies to date have investigated the characteristics of both recurrence and relapse in OIS. We sought to determine this in both pediatric and adult patients. METHODS: A retrospective chart review of 56 patients with OIS was performed between 2004 and 2018. Forty-one patients were identified as adults greater than 18 years of age and 15 were identified as pediatric patients less than 18 years of age. RESULTS: Among 56 (41 adult and 15 pediatric) cases of OIS, 18 cases of recurrent disease (32.1%) were identified and 15 (26.8%) patients experienced relapses. All 6 (100%) pediatric patients that had recurrent disease initially suffered from relapses. In contrast, only 1 of the 12 (8.3%) recurrent adult cases initially experienced relapse. Of the 18 patients with recurrent disease, 9 (50%) had multiple recurrences. Underlying etiologies were confirmed in 5 of 18 recurrent cases (27.8%) and 5 of 38 (13.2%) non-recurrent cases. Of the 5 patients with recurrent OIS and an identified etiology, all 5 (100%) demonstrated multiple recurrences. CONCLUSIONS: In pediatric cases, relapse was more common and prior episodes of relapse were predictive of later recurrence. Recurrence was relatively common in both groups with half of the patients having multiple recurrences. Identifiable underlying etiologies were more common in patients with recurrent OIS and those cases all demonstrated multiple recurrences.