Potent antiarthritic properties of a glucocorticoid derivative, NCX-1015, in an experimental model of arthritis

Paul-Clark, Mark J.; Mancini, L.; Soldato, Piero Del; Flower, Roderick J.; Perretti, Mauro

doi:10.1073/pnas.022641099

Cited by 75 publications

(60 citation statements)

References 33 publications

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“…It has been shown in murine arthritis models that NCX-1015 caused anti-inflammatory effects 10-fold stronger than conventional prednisolone. At the same time fewer side effects are anticipated on the bone compartment, since elevated bone resorbing activity of rat primary osteoclasts was observed for prednisolone but not for NCX-1015 [42][43][44]. In order to explain the strong anti-inflammatory effects of nitro-steroids, posttranslational modification of GCR through tyrosine nitration is suggested [42].…”

Section: Nitro-steroidsmentioning

confidence: 99%

Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists

Stahn

Löwenberg

Hommes

et al. 2007

Molecular and Cellular Endocrinology

337

266

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To cite this version:Cindy Stahn, Mark Löwenberg, Daniel W. Hommes, Frank Buttgereit. Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists. Molecular and Cellular Endocrinology, Elsevier, 2007, 275 (1-2) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.A c c e p t e d M a n u s c r i p t promising results. Here, we review the above mentioned mechanisms of glucocorticoid action and give particular attention to the development of optimized glucocorticoids and SEGRA's.

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Section: Nitro-steroidsmentioning

confidence: 99%

Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists

Stahn

Löwenberg

Hommes

et al. 2007

Molecular and Cellular Endocrinology

337

266

View full text Add to dashboard Cite

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“…We also observed a significant reduction in systemic toxicity of the NO-releasing derivative of flunisolide versus the parent drug; thus, adrenal atrophy and the reduction of body weight gain associated with daily administration of flunisolide were substantially reduced in rats treated with NCX-1024. In studies of NO-releasing prednisolone, Paul-Clark et al (2002) observed a significant reduction of collagen-induced arthritis associated bone and cartilage erosion in comparison with that seen in rats treated with prednisolone.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Anti-Inflammatory Potency of a Nitric Oxide-Releasing Derivative of Flunisolide: Role of Nuclear Factor-κB

Wallace¹,

Rizzo²,

Cirino³

et al. 2004

J Pharmacol Exp Ther

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Glucocorticoids remain among the most commonly used antiinflammatory drugs, despite significant adverse effects. Other anti-inflammatory drugs, including aspirin, have been coupled through an ester linkage to a nitric oxide-releasing moiety, resulting in an increase in potency and a decrease in adverse effects. Prednisolone has similarly been modified, with marked improvement of its therapeutic index. In the present study, we have evaluated whether a nitric oxide-releasing derivative of another glucocorticoid, flunisolide, would increase its potency as an anti-inflammatory agent and would decrease its systemic toxicity. To evaluate anti-inflammatory potency and efficacy, the carrageenan-airpouch model in the rat was used. Flunisolide and NCX-1024 (flunisolide-21-[4Ј-(nitrooxymethyl) benzoate]) were compared across a range of doses, with both direct injection into the airpouch and oral administration. The ability of these agents to protect the stomach against indomethacininduced damage also was assessed. Effects of oral administration of the two drugs on body weight gain and adrenal suppression were also evaluated. With direct application into the airpouch, NCX-1024 was found to be 41 times more potent than flunisolide in reducing leukocyte accumulation and prostaglandin E 2 generation. The increased potency may be related to an enhanced ability of NCX-1024 to prevent nuclear factor-B activation. When given orally, the two compounds exhibited similar potency. However, orally administered NCX-1024 was more potent at protecting against indomethacininduced gastric damage, caused less reduction of body weight, and, unlike flunisolide, did not cause adrenal atrophy. These studies suggest that NCX-1024 may be an attractive alternative to conventional glucocorticoids, particularly for applications involving topical administration.

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“…Plasma levels of osteocalcin, a marker of bone formation, were determined using a commercially available IRMA specific for rats (Immutopics, San Clemente, CA). A competitive enzyme immunoassay (Metra Biosystems, Mountain View, CA) was used to evaluate pyridinoline, a marker of cartilage and bone destruction (29)(30)(31)(32).…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, serum pyridinoline levels increased almost 2-fold during the chronic phase of SCW arthritis ( Figure 4A). Treatment with PTHrP antibody inhibited the SCW-induced increase in pyridinoline, a degradation product of cartilage and bone that correlates with destruction of both of these tissues in animal models of arthritis (29)(30)(31)(32) (Figure 4A). …”

Section: Pthrp Expression In Scw-induced Arthritismentioning

confidence: 99%

Blockade of parathyroid hormone–related protein prevents joint destruction and granuloma formation in streptococcal cell wall–induced arthritis

Funk¹,

Chen²,

Downey³

et al. 2003

Arthritis & Rheumatism

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Objective. To determine whether parathyroid hormone-related protein (PTHrP), an interleukin-1␤-inducible, bone-resorbing peptide that is produced in increasing amounts by the synovium in rheumatoid arthritis (RA), may play a role in the pathophysiology of joint destruction in RA.Methods. PTHrP expression and the effect of PTHrP 1-34 neutralizing antibody on disease progression were tested in streptococcal cell wall (SCW)-induced arthritis, an animal model of RA.Results. As has been reported in RA, while serum levels of PTHrP did not change during SCW-induced arthritis, PTHrP expression dramatically increased in the arthritic synovium. Treatment with PTHrP neutralizing antibody (versus control antibody) did not affect joint swelling in SCW-treated animals. However, PTHrP antibody significantly inhibited SCW-induced joint destruction, as measured by its ability to block increases in serum pyridinoline (a marker of cartilage and bone destruction), erosion of articular cartilage, decreases in femoral bone mineral density, and increases in the numbers of osteoclasts in eroded bone. Unexpectedly, granuloma formation at sites of SCW deposition in the liver and spleen was also inhibited by PTHrP antibody, an effect associated with significant decreases in the tissue influx of PTH/PTHrP receptor-positive neutrophils and in SCW-induced neutrophilia. In vitro, neutrophil chemotaxis was stimulated by PTHrP 1-34.Conclusion. These findings suggest that PTHrP, consistent with its previously described osteolytic effects in metastatic bone disease, can also be an important mediator of joint destruction in inflammatory bone disorders, such as RA. Moreover, this study reveals heretofore unknown effects of PTHrP peptides on neutrophil function that could have important implications in the pathogenesis of inflammatory granulomatous disorders.

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Potent antiarthritic properties of a glucocorticoid derivative, NCX-1015, in an experimental model of arthritis

Cited by 75 publications

References 33 publications

Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists

Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists

Enhanced Anti-Inflammatory Potency of a Nitric Oxide-Releasing Derivative of Flunisolide: Role of Nuclear Factor-κB

Blockade of parathyroid hormone–related protein prevents joint destruction and granuloma formation in streptococcal cell wall–induced arthritis

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