Supplement Article |
OP25. NEW GLUCOCORTICOIDS: SELECTIVE GLUCOCORTICOID RECEPTOR AGONISTS, NO-GLUCOCORTICOIDS AND LONG-CIRCULATING LIPOSOMAL GLUCOCORTICOIDS
Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, Germany
Our understanding of the actions of glucocorticoids has greatly increased in the last few years. The various genomic and non-genomic mechanisms of glucocorticoid action provide interesting and sometimes very advanced starting points for the development of optimised glucocorticoids and glucocorticoid receptor ligands. SEGRAs, NO-glucocorticoids and long-circulating liposomal glucocorticods are examples to be mentioned in this regard.
Selective glucocorticoid receptor agonists (SEGRAs): Currently glucocorticoid receptor ligands are being developed that cause predominantly transrepression but not transactivation. These drugs are called selective glucocorticoid receptor agonists (SEGRAs) and are thought to have an improved safety/efficacy profile. In vivo investigations and clinical trials will have to define whether SEGRAs will, as ‘improved glucocorticoids’, enter clinical medicine in the near future.
NO-glucocorticoids: Recent experimental observations prompt the assessment of the clinical impact of another new class of glucocorticoid drugs, NO-glucocorticoids, which are able to release low levels of nitric oxide. They have been shown to be endowed with enhanced anti-inflammatory properties and reduced side effects. The prototype of these new steroids, 21-NO-prednisolone, is much more potent than prednisolone in models of acute and chronic inflammation but does not activate primary osteoclast activity (whereas prednisolone does). However, more studies are needed to confirm that NO-glucocorticoids will be effective as anti-inflammatory agents in clinical practice.
Long-circulating liposomal glucocorticoids: The anti-inflammatory effectiveness of glucocorticoids can be improved by the additional benefits of the non-genomic actions of high glucocorticoid concentrations. On this basis, the successful use of long-circulating liposomal glucocorticoids has recently been reported which accumulate at sites of inflammation. This leads to very high glucocorticoid concentrations at e.g. the inflamed joint (but accompanied by low plasma concentrations with perhaps a lower rate of side effects) which is the key factor explaining the observed strong therapeutic effect.
Conclusions: These new GCR-ligands and the administration of liposomes are very promising approaches that will hopefully soon be available in clinical practice to improve the benefit/risk ratio and well-being of patients being treated. Another intriguing issue is the study of membrane bound glucocorticoid receptors (mGCR). These surface receptors are suggested to mediate rapid nongenomic effects and have been found to be upregulated in active rheumatoid arthritis. The number of monocytes expressing mGCR is significantly correlated with disease activity. Therefore, drugs binding selectively to the mGCR may in future also prove to be of therapeutic value but the functions of mGCR must first be investigated in detail.