1. Initiation of a peritoneal
Arthus reaction by deposition of
immune-complexes results in vascular leakage, polymorphonuclear leukocyte (PMN) infiltration, and tumour
necrosis factor alpha (
TNFalpha) and
interleukin-6 (IL-6) production. We now demonstrate in rats that
oral administration of the
C5a receptor antagonist AcPhe[Orn-Pro-D-
Cyclohexylalanine-Trp-Arg] (
AcF-[OPdChaWR]; 1 - 10 mg kg(-1) 30 min prior to
immune-complex deposition) inhibits these inflammatory markers in the peritoneal
Arthus reaction. 2. Initiation of a dermal
Arthus reaction resulted in a significant increase in vascular leakage, PMN infiltration, systemic production of
TNFalpha and pathological changes in the dermis. 3. Pretreatment of rats with
AcF-[OPdChaWR] either intravenously (1 mg kg(-1) 10 min prior to
immune-complex deposition) or orally (1 - 10 mg kg(-1) 30 min prior to
immune-complex deposition) significantly inhibited
immune-complex mediated dermal vascular leakage and systemic
cytokine production. Topical pretreatment with
AcF-[OPdChaWR] (400 microg site(-1) in 10%
dimethyl sulphoxide 10 min prior to
immune-complex deposition) also inhibited vascular leakage, as well as histopathological changes associated with a dermal
Arthus reaction. 4.
Oral administration of 3 mg kg(-1)
AcF-[OPdChaWR] resulted in the appearance of the
drug in plasma within 5 min, with peak blood levels approximately 0.3 microM reached within 20 min. The plasma elimination half-life was approximately 70 min. The oral activity and bioavailability of
AcF-[OPdChaWR], its activity when applied topically to the skin, suggest that small molecule
C5a receptor antagonists may have therapeutic utility in dermal inflammatory disorders involving complement activation. 5. This is the first demonstration for either an orally or topically active
C5a receptor antagonist, and suggests that small molecule C5a antagonists may have therapeutic utility when given by multiple routes of application.