New, safer glucocorticoids may be on the horizon

[Guest guest]

New, safer glucocorticoids may be on the horizon

Aug 4, 2005 Janis

Berlin, Germany - The glucocorticoids provide treatment efficacy

equaled by few other drug classes, but at a price in side effects that

many patients are loathe to pay. While new drugs such as the TNF

inhibitors have attracted the most attention, researchers working on

better versions of the " old " glucocorticoids have been quietly

progressing on several fronts. Dr In-Ho Song (Charité University

Hospital, Berlin, Germany) and colleagues review the state of the art

in the Journal of Rheumatology [1].

" In the field of 'good old glucocorticoids,' developments are taking

place that are potentially very exciting. Even if only one of the

innovations described here comes to fruition, greatly improved

glucocorticoids will be available to us. If we could use

glucocorticoids in high doses for an unlimited length of time, much of

the concern about the treatment of our patients with rheumatic disease

could be eliminated, " Song writes.

Major pharma researchers hot on heels of better steroids

One indication of the importance of this area is the significant

resources the major pharmaceutical companies are devoting to it. In a

recent brief literature search, rheumawire found studies from

researchers at Merck, Schering, Pfizer, and Ligand Pharmaceuticals Inc.

Current studies fall into two general areas: those that focus on the

gene-modulating actions of glucocorticoids, and those that cause

specific nongenomic actions mediated through membrane-bound

glucocorticoid receptors (mGCRs). Song discusses the following products

in development:

* Selective glucocorticoid receptor agonists (SEGRAs) or

dissociating glucocorticoids.

* Nitrosteroids.

* Long-circulating liposome glucocorticoids.

* Membrane-bound glucocorticoid receptor ligands.

The first three areas rest on the recent discovery that glucocorticoids

induce two types of genomic actions: transactivation (which increases

expression of target genes) and transrepression (which represses target

genes). " In recent years, it has become clear that a large number of

the desirable anti-inflammatory and immunomodulating actions of

glucocorticoids are due to transrepression, while a large proportion of

the adverse reactions are due to transactivation, " Song writes.

The SEGRAs were discovered as a result of the search for

transrepressing steroids. These molecules bind selectively to the

glucocorticoid receptor and induce transrepression but have little

effect on transactivation. Several of these compounds tested in animal

models have supported the hypothesis that inducing transrepression

without transactivation would retain anti-inflammatory effects without

causing side effects such as osteopenia or weight changes.

If we could use glucocorticoids in high doses for an unlimited length

of time, much of the concern about the treatment of our patients with

rheumatic disease could be eliminated.

Nitrosteroids (NO-glucocorticosteroids) try to harness the

anti-inflammatory effects of nitric oxide, which include reduced

leukocyte adhesion to the endothelium, reduced leukocyte extravasation,

and suppression of the synthesis of inflammatory mediators.

Nitrosteroids are glucocorticoid derivatives coupled to a linker

molecule that binds NO, which is then released slowly and produces a

prolonged anti-inflammatory effect. Song says that this approach has

been successful in animal models of peritonitis and colitis and that NO

has a synergistic anti-inflammatory effect with the glucocorticoids.

Liposomal glucocorticoids are being developed to produce higher,

sustained glucocorticoid levels able to inhibit the activity of

previously activated immune cells, in part by intercalating into and

stabilizing cell membranes. Liposomes are also under investigation as

targeting agents to achieve selective accumulation and high

concentrations of glucocorticoids at sites of inflammation.

Song's group has added to the new glucocorticoid possibilities by

identifying an mGCR on human peripheral blood monocytes [2]. Expression

of this receptor is upregulated in rheumatoid arthritis (RA) patients.

" Our data indeed showed a strong positive correlation between the

frequency of mGCR-positive monocytes and various disease-activity

indicators, " Song writes. This suggests that drugs selectively binding

to the mGCR might be useful in treating RA.

Sources

1. Song IH, Gold R, Straub RH, et al. New glucocorticoids on the

horizon: Repress, don't activate! J Rheumatol 2005; 32:1199-1207.

2. Bartholome B, Spies CM, Gaber T, et al. Membrane glucocorticoid

receptors (mGCR) are expressed in normal human peripheral blood

mononuclear cells and up-regulated after in vitro stimulation and in

patients with rheumatoid arthritis. FASEB J 2004; 18:70-80.