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Although introduced more than 50 years ago, topical glucocorticoids are still the first line therapy for many inflammatory skin disorders such as atopic eczema, contact dermatitis and many others. Recently, significant improvements have been made to optimize the ratio of desired to unwanted effects. While with early compounds such as triamcinolone, topical side effects such as skin atrophy and telangiectasias can be observed rather frequently, newer drugs such as methylprednisolone aceponate or mometasone furoate have a significantly improved therapeutic index. The present study compared these two modern topical glucocorticoids, which possess the highest therapeutic index currently found, in terms of nuclear receptor selectivity in vitro and induction of the most important local side effects (skin atrophy and telangiectasias) in a relevant rodent model in vivo. We demonstrate that methylprednisolone aceponate displays higher specificity in nuclear receptor binding compared with mometasone furoate. Methylprednisolone aceponate was also markedly superior in terms of minimizing induction of skin atrophy or telangiectasias when compared with mometasone furoate. Based on these observations, methylprednisolone aceponate is expected to have a greater therapeutic index as compared with mometasone furoate, at least in the test systems used here. The degree to which this observation may translate into a clinical setting requires confirmation.

Glucocorticoids are well known for their potent anti-inflammatory and immune-suppressive actions. Their clinical usefulness remains limited due to serious side effects that have necessitated a search for ways of improving their benefit-risk ratios. Mechanistically, glucocorticoids function by interacting with an intracellular receptor, the glucocorticoid receptor, a ligand-regulated transcription factor that positively or negatively alters the expression of specific genes. While it is well accepted that distinct negative regulatory action of this receptor forms the basis of the desired anti-inflammatory effects of glucocorticoids, not much is known about the function of the receptor that contributes to its side effects. The fact that a number of cellular metabolic control genes are positively regulated by glucocorticoids makes positive regulation of gene expression an attractive mode of action for the adverse effects. Positive regulation of gene expression by glucocorticoids, however, occurs through different mechanisms and in cell-type specific manner making it difficult to predict its possible biological effects in one single assay procedure. Recent advances in the molecular action of the receptor are gradually revealing different assays and important characteristics that can be put together in determining the physiological consequences of the different transactivation functions of the glucocorticoid receptor. These will provide invaluable source of information for the search of glucocorticoid receptor agonists with potent anti-inflammatory but reduced side effects.

The current standard systemic therapeutic modalities for psoriasis have many potential side effects. Progress made in the understanding of the pathophysiology of psoriasis as a T-cell-mediated dermatosis provide options for new more precise therapeutic approaches. These immunological therapeutic strategies involve the inhibition/depletion of activated T-lymphocytes, the inhibition of antigen presentation and thus the regulation of T-cell activation, the inhibition of adhesion of inflammatory cells, the inhibition of effects of proinflammatory mediators and the administration of antiinflammatory cytokines. This article summarizes these new systemic therapeutic approaches. Clinical results in the early studies have been mixed. In the next years further results of phase II- and phase Ill-studies may be expected, which should allow better assessment of the potential of those particular approaches. Some of these approaches could lead to the approval of new drugs to treat psoriasis and to enhance or replace already existing therapeutic options. Furthermore results of therapeutic experiments should contribute to a better understanding of the disease. As we learn which mechanisms are more or less important for the disease, we will be better able to plan intervention strategies.

Glucocorticoids (GCs) represent the most important and frequently used class of anti-inflammatory drugs. While the therapeutic effects of GCs have been known and used for more than 50 years, major progress in discovering the underlying molecular mechanisms has only been made in the last 10-15 years. There is consensus that the desired anti-inflammatory effects of GCs are mainly mediated via repression of gene transcription. In contrast, the underlying molecular mechanisms for GC-mediated side effects are complex, distinct, and frequently only partly understood. Recent data suggest that certain side effects are predominantly mediated via transactivation (e.g., diabetes, glaucoma), whereas others are predominantly mediated via transrepression (e.g., suppression of the hypothalamic-pituitary-adrenal axis). For a considerable number of side effects, the precise molecular mode is either so far unknown or both transactivation and transrepression seem to be involved (e.g., osteoporosis). The differential molecular regulation of the major anti-inflammatory actions of GCs and their side effects is the basis for the current drug-finding programs aimed at the development of dissociated GC receptor (GR) ligands. These ligands preferentially induce transrepression by the GR, but only reduced or no transactivation. This review summarizes the current knowledge of the most important GC-mediated side effects from a clinical to a molecular perspective. The focus on the molecular aspects should be helpful in predicting the potential advantages of selective GR agonists in comparison to classical GCs.

Glucocorticoids are highly effective in the therapy of inflammatory and autoimmune disorders. Their beneficial action is restricted because of their adverse effects upon prolonged usage. Topical glucocorticoids that act locally have been developed to significantly reduce systemic side effects. Nonetheless, undesirable cutaneous effects such as skin atrophy persist from the use of topical glucocorticoids. There is therefore a high medical need for drugs as effective as glucocorticoids but with a reduced side-effect profile. Glucocorticoids function by binding to and activating the glucocorticoid receptor that positively or negatively regulates the expression of specific genes. Several experiments suggest that the negative regulation of gene expression by the glucocorticoid receptor accounts for its anti-inflammatory action. This occurs through direct or indirect binding of the receptor to transcription factors such as activator protein-1, nuclear factor- κB or interferon regulatory factor-3 that are already bound to their regulatory sites. The positive action of the receptor occurs through homodimer binding of the receptor to discrete nucleotide sequences and this possibly contributes to some of the adverse effects of the hormone. Glucocorticoid receptor ligands that promote the negative regulatory action of the receptor with reduced positive regulatory function should therefore show improved therapeutic potential. A complete separation of the positive from the negative regulatory activities of the receptor has so far not been possible because of the interdependent nature of the two regulatory processes. Nevertheless, considerable improvement in the therapeutic action of glucocorticoid receptor ligands is being achieved through the use of key molecular targets for screening novel glucocorticoid receptor ligands. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) are highly effective for the topical treatment of inflammatory skin diseases. Their long-term use, however, is often accompanied by severe and partially irreversible adverse effects, with atrophy being the most prominent limitation. Progress in the understanding of GC-mediated molecular action as well as some advances in technologies to determine the atrophogenic potential of compounds has been made recently. It is likely that the detailed mechanisms of GC-induced skin atrophy will be discovered and in vitro models for the reliable prediction of atrophy will be established in the foreseeable future. This knowledge will not only facilitate safety profiling of established drugs but will also foster further drug discovery by improving compound characterization processes. New insights into GC modes of action will guide optimization strategies aiming at novel GC receptor ligands with improved effect/side effect profile. [ABSTRACT FROM AUTHOR]

Summarizes advances in animal research that are important for anti-inflammatory drug discovery. Common features of inflammatory disease models; Modeling of atopic dermatitis; Allergic contact dermatitis.

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. [ABSTRACT FROM AUTHOR]

Inhibition of leukocyte migration into target organs has long been an attractive, though challenging, basis for anti-inflammatory strategies. However, to date, the manipulation of leukocyte rolling along blood vessels has not yielded successful new therapies. An important study (see the related article beginning on page 1008) may now open new avenues in this exciting field of anti-inflammatory therapies by introducing a putative inhibitor of poly-N-acetyllactosamine biosynthesis that affects selectin ligand activity and shows efficacy in a rodent skin inflammation model. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) belong to the most widely used anti-inflammatory drugs at all. However, their topical use is limited by their side effect potential, with skin atrophy being the most prominent one. Thus, determining the atrophogenic potential of novel compounds is of importance for drug development. Currently, the most frequently performed model in the base and pharmaceutical research is the hr/hr rat model of GC-induced skin atrophy that lasts for 19 days. In this study, we analysed statistically skin atrophy experiments retrospectively to ascertain (i) the earliest time-point, at which skin atrophy is significantly induced; and (ii) whether the differences between the GC treatment groups change until the end of the experiment. We show here that the treatment duration of rat skin atrophy models might be reduced to 5 days for economical and ethical reasons. [ABSTRACT FROM AUTHOR]