Characterization of ZK 245186, a novel,selective glucocorticoid receptor agonist for the topical treatment of inflammatory skin diseases

Background and purpose:

Glucocorticoids are highly effective in the therapy of inflammatory diseases. Their value, however, is limited by side effects. The discovery of the molecular mechanisms of the glucocorticoid receptor and the recognition that activation and repression of gene expression could be addressed separately opened the possibility of achieving improved safety profiles by the identification of ligands that predominantly induce repression. Here we report on ZK 245186, a novel, non-steroidal, low-molecular-weight, glucocorticoid receptor-selective agonist for the topical treatment of inflammatory dermatoses.

Experimental approach:

Pharmacological properties of ZK 245186 and reference compounds were studied in terms of their potential anti-inflammatory and side effects in functional bioassays in vitro and in rodent models in vivo.

Key results:

Anti-inflammatory activity of ZK 245186 was demonstrated in in vitro assays for inhibition of cytokine secretion and T cell proliferation. In vivo, using irritant contact dermatitis and T cell-mediated contact allergy models in mice and rats, ZK 245186 showed anti-inflammatory efficacy after topical application similar to the classical glucocorticoids, mometasone furoate and methylprednisolone aceponate. ZK 245186, however, exhibits a better safety profile with regard to growth inhibition and induction of skin atrophy after long-term topical application, thymocyte apoptosis, hyperglycaemia and hepatic tyrosine aminotransferase activity.

Conclusions and implications:

ZK 245186 is a potent anti-inflammatory compound with a lower potential for side effects, compared with classical glucocorticoids. It represents a promising drug candidate and is currently in clinical trials.This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009     

Exploring NT-proBNP,syndecan-1, and cytokines as biomarkers for transfusion-associated circulatory overload in a critically ill patient population receiving a single-unit red blood cell transfusion

Background

Transfusion-associated circulatory overload (TACO) is an often underdiagnosed pulmonary transfusion complication. A biomarker could aid with the diagnosis. To date, B-type natriuretic peptide (BNP) and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) seem the most promising biomarkers in the general hospital population. The aim was to evaluate NT-proBNP as a biomarker for TACO in a critically ill patient population and explore syndecan-1 and cytokines as other potential biomarkers.

Study Design and Methods

A retrospective study was performed using samples and clinical data collected during a prospective observational study. Adult patients admitted to the intensive care and transfused with a single red blood cell unit were included. TACO cases were retrospectively identified using a case definition based on the current TACO definition. The primary biomarker was NT-proBNP, also we measured syndecan-1 IL-6, IL-8, and IL-10. All markers were measured directly before transfusion, 1 and 24 h after transfusion.

Results

Our cohort included 64 patients, 12 of which were identified as TACO patients. TACO patients had a lower PaO₂/FiO₂ ratio and were more often ventilated following transfusion compared to non-TACO patients. There was no significant difference in NT-proBNP between pre- and post-transfusion levels nor between TACO and non-TACO patients. Syndecan-1 was significantly elevated in TACO patients both pre- and post-transfusion compared to non-TACO patients.

Discussion

NT-proBNP was not associated with TACO in this critically ill patient population. Interestingly, levels of syndecan-1 were increased in TACO patients at baseline. More research is needed to clarify this association and its possibilities as a biomarker to predict patients at risk for TACO.