Antiarthritic activity of an orally active C5a receptor antagonist against antigen-induced monarticular arthritis in the rat

Woodruff, Trent M., Strachan, Anna J., Dryburgh, Nathan, Shiels, Ian A., Reid, Robert C., Fairlie, David P. and Taylor, Stephen M. (2002) Antiarthritic activity of an orally active C5a receptor antagonist against antigen-induced monarticular arthritis in the rat. Arthritis and Rheumatism, 46 9: 2476-2485. doi:10.1002/art.10449


Author Woodruff, Trent M.
Strachan, Anna J.
Dryburgh, Nathan
Shiels, Ian A.
Reid, Robert C.
Fairlie, David P.
Taylor, Stephen M.
Title Antiarthritic activity of an orally active C5a receptor antagonist against antigen-induced monarticular arthritis in the rat
Journal name Arthritis and Rheumatism   Check publisher's open access policy
ISSN 0004-3591
1529-0131
0893-7524
Publication date 2002-09-01
Sub-type Article (original research)
DOI 10.1002/art.10449
Volume 46
Issue 9
Start page 2476
End page 2485
Total pages 10
Place of publication Hoboken. NJ., U.S.A.
Publisher American College of Rheumatology
Language eng
Subject C1
320503 Clinical Pharmacology and Therapeutics
730114 Skeletal system and disorders (incl. arthritis)
1103 Clinical Sciences
Formatted abstract
Objective: To determine if the new, orally active C5a receptor antagonist, the cyclic peptide AcF-[OPdChaWR], reduces the severity of pathology in a rat model of immune-mediated monarticular arthritis.

Methods: Arthritis was induced in the right knee of previously sensitized rats by the intraarticular injection of methylated bovine serum albumin. Rats were examined for either 14 days or 28 days, or for 49 days following a second antigen challenge at 28 days. The C5a antagonist (1 or 3 mg/kg/day) and/or ibuprofen (30 mg/kg/day) were administered orally on a daily basis either before or after arthritis induction.

Results: Rats receiving AcF-[OPdChaWR] had significant reductions in right knee swelling, gait disturbance, lavaged joint cell numbers, and right knee histopathology, as well as in serum levels of tumor necrosis factor α (TNFα) and intraarticular levels of interleukin-6 and TNFα on day 14. In the 14- and 28-day studies, ibuprofen resulted in a similar reduction in gait abnormalities and intraarticular inflammatory cells compared with the C5a antagonist, but was less effective in reducing knee swelling over the course of the study and had no effect on knee histopathology. Combination therapy with AcF-[OPdChaWR] and ibuprofen resulted in no greater efficacy than with the C5a antagonist alone. Rats injected twice with the antigen in the 49-day study displayed the most severe histopathology and this, as well as knee swelling and gait abnormalities, was significantly reduced by repeated treatment with the C5a antagonist.
Conclusion:  An agent that inhibits the action of C5a in this model significantly reduced joint pathology, while ibuprofen was not effective. C5a antagonists could therefore have broader therapeutic benefits than nonsteroidal antiinflammatory drugs as antiarthritic agents for rheumatoid arthritis.
Copyright © 2010 American College of Rheumatology

Keyword Rheumatology
Collagen-induced Arthritis
Synovial-fluid Levels
Rheumatoid-arthritis
Polymorphonuclear Leukocytes
Complement Pathway
Inhibition
Neutrophil
Disease
Shock
Degradation
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
Institute for Molecular Bioscience - Publications
 
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Created: Wed, 15 Aug 2007, 05:02:46 EST