Arndt Schottelius

Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects

Glucocorticoids (GCs) are the most commonly used antiinflammatory and immunosuppressive drugs. Their outstanding therapeutic effects, however, are often accompanied by severe and sometimes irreversible side effects. For this reason, one goal of research in the GC field is the development of new drugs, which show a reduced side-effect profile while maintaining the antiinflammatory and immunosuppressive properties of classical GCs. GCs affect gene expression by both transactivation and transrepression mechanisms. The antiinflammatory effects are mediated to a major extent via transrepression, while many side effects are due to transactivation. Our aim has been to identify ligands of the GC receptor (GR), which preferentially induce transrepression with little or no transactivating activity. Here we describe a nonsteroidal selective GR-agonist, ZK 216348, which shows a significant dissociation between transrepression and transactivation both in vitro and in vivo. In a murine model of skin inflammation, ZK 216348 showed antiinflammatory activity comparable to prednisolone for both systemic and topical application. A markedly superior side-effect profile was found with regard to increases in blood glucose, spleen involution, and, to a lesser extent, skin atrophy; however, adrenocorticotropic hormone suppression was similar for both compounds. Based on these findings, ZK 216348 should have a lower risk, e.g., for induction of diabetes mellitus. The selective GR agonists therefore represent a promising previously undescribed class of drug candidates with an improved therapeutic index compared to classical GCs. Moreover, they are useful tool compounds for further investigating the mechanisms of GR-mediated effects.

Biology of tumor necrosis factor‐α– implications for psoriasis

Abstract:  Numerous recent investigations have pointed to a key role of the proinflammatory, pleiotropic cytokine tumor necrosis factor‐α (TNF‐α) in host defense and inflammatory processes. TNF overexpression has been found in lesional skin and in the circulation of psoriatic patients, and it was suggested that TNF‐α is crucial in this and other immune diseases. Several approaches to inhibit TNF‐α activity have been developed. These include three different neutralizing antibodies to TNF‐α as well as three different soluble TNF‐α receptors with characteristic properties designed to bind the 17‐KDa soluble trimeric TNF‐α and the 26‐KDa membrane‐bound form of TNF‐α. Clinical trials have demonstrated significant antipsoriatic effects, and it is likely that blocking TNF‐α will become an important therapeutic option. The data available from these trials contribute to further understanding of the disease by demonstrating the major role of TNF‐α. An in‐depth understanding of the regulation of TNF gene expression, protein production, receptor expression, and signaling pathways may lead to further, potentially important novel therapeutic strategies and antipsoriatic active small molecules, suitable for oral application in the future. Here we review the current knowledge of TNF biology, the approaches to inhibit TNF activity, and their clinical and immunological effects in psoriasis. In addition, the host‐defense effects and chronic TNF‐blocking activity are discussed.

An Aspirin-Triggered Lipoxin A4 Stable Analog Displays a Unique Topical Anti-Inflammatory Profile

Lipoxins and 15-epi-lipoxins are counter-regulatory lipid mediators that modulate leukocyte trafficking and promote the resolution of inflammation. To assess the potential of lipoxins as novel anti-inflammatory agents, a stable 15-epi-lipoxin A4 analog, 15-epi-16-p-fluorophenoxy-lipoxin A4 methyl ester (ATLa), was synthesized by total organic synthesis and examined for efficacy relative to a potent leukotriene B4 (LTB4) receptor antagonist (LTB4R-Ant) and the clinically used topical glucocorticoid methylprednisolone aceponate. In vitro, ATLa was 100-fold more potent than LTB4R-Ant for inhibiting neutrophil chemotaxis and trans-epithelial cell migration induced by fMLP, but was ∼10-fold less potent than the LTB4R-Ant in blocking responses to LTB4. A broad panel of cutaneous inflammation models that display pathological aspects of psoriasis, atopic dermatitis, and allergic contact dermatitis was used to directly compare the topical efficacy of ATLa with that of LTB4R-Ant and methylprednisolone aceponate. ATLa was efficacious in all models tested: LTB4/Iloprost-, calcium ionophore-, croton oil-, and mezerein-induced inflammation and trimellitic anhydride-induced allergic delayed-type hypersensitivity. ATLa was efficacious in mouse and guinea pig skin inflammation models, exhibiting dose-dependent effects on edema, neutrophil or eosinophil infiltration, and epidermal hyperproliferation. We conclude that the LXA4 and aspirin-triggered LXA4 pathways play key anti-inflammatory roles in vivo. Moreover, these results suggest that ATLa and related LXA4 analogs may have broad therapeutic potential in inflammatory disorders and could provide an alternative to corticosteroids in certain clinical settings.