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01-04-2011 | Research Article

Attenuation of arthritis in rodents by a novel orally-available inhibitor of sphingosine kinase

Authors: Leo R. Fitzpatrick, Cecelia Green, Elizabeth E. Frauenhoffer, Kevin J. French, Yan Zhuang, Lynn W. Maines, John J. Upson, Emmanuel Paul, Henry Donahue, Timothy J. Mosher, Charles D. Smith

Published in: Inflammopharmacology | Issue 2/2011

Abstract

Pro-inflammatory cytokines like TNF-α activate sphingosine kinase (SK). Therefore, inhibition of SK is a potential molecular target for the treatment of rheumatoid arthritis.

Aims

The primary goal of this study was to assess the efficacy of ABC249640 (a selective SK-2 inhibitor) in two models of rodent arthritis. A secondary goal was to evaluate the pharmacological profile of ABC294640, when given in combination with methotrexate.

Methods

The efficacy of ABC294640 was determined by paw diameter/volume measurements, histological evaluations, and micro-CT analyses.

Results

ABC294640 attenuated both collagen-induced arthritis in mice, as well as adjuvant-induced arthritis in rats. With the adjuvant arthritis model, the prophylactic efficacy profile of ABC294640 was similar to indomethacin. Of note, ABC294640 reduced the bone and cartilage degradation, associated with adjuvant-induced arthritis. Rats treated with a suboptimal dose of MTX (50 μg/kg/day) in combination with ABC249640 (100 mg/kg/day) had better anti-arthritis effects in the adjuvant model, than treatment with either agent alone.

Conclusion

Our results suggest that ABC249640 is an orally available drug candidate with a good pre-clinical efficacy profile for the prevention and/or treatment of RA.

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Title: Attenuation of arthritis in rodents by a novel orally-available inhibitor of sphingosine kinase
Authors: Leo R. Fitzpatrick
Cecelia Green
Elizabeth E. Frauenhoffer
Kevin J. French
Yan Zhuang
Lynn W. Maines
John J. Upson
Emmanuel Paul
Henry Donahue
Timothy J. Mosher
Charles D. Smith
Publication date: 01-04-2011
Publisher: SP Birkhäuser Verlag Basel
Published in: Inflammopharmacology / Issue 2/2011
Print ISSN: 0925-4692
Electronic ISSN: 1568-5608
DOI: https://doi.org/10.1007/s10787-010-0060-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Attenuation of arthritis in rodents by a novel orally-available inhibitor of sphingosine kinase

Abstract

Aims

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Aims

Methods

Results

Conclusion

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