Antiarthritic activity of an orally active C5a receptor antagonist against antigen-induced monarticular arthritis in the rat.
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 alpha (TNFalpha) and intraarticular levels of interleukin-6 and TNFalpha 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.


CONCLUSIONS
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.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000941:Antigens / Q000276:immunology*; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D015936:Complement C5a / Q000378:metabolism*; D004359:Drug Therapy, Combination; D005260:Female; D007052:Ibuprofen / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011951:Receptors, Complement / Q000037:antagonists & inhibitors*; D012710:Serum Albumin, Bovine; D013997:Time Factors
C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); D000894:Anti-Inflammatory Agents, Non-Steroidal; D000941:Antigens; D010456:Peptides, Cyclic; D011951:Receptors, Complement; D012710:Serum Albumin, Bovine; D015936:Complement C5a; D007052:Ibuprofen