Anti-inflammatory synergy of MEN16132, a kinin B(2) receptor antagonist, and dexamethasone in carrageenan-induced knee joint arthritis in rats.
OBJECTIVE
Bradykinin, through its B(2) receptor, is involved in inflammatory processes related to arthropathies. In carrageenan and lipopolysaccharide (LPS)-induced arthritis in rat, the anti-inflammatory activity of MEN16132, a potent and selective kinin B(2) receptor antagonist, was compared with that of steroidal and nonsteroidal anti-inflammatory drugs. The interaction between MEN16132 and dexamethasone was also investigated.


METHODS
Drugs, alone or in combination, were injected into the knee joint 30min before intra-articular administration of carrageenan or LPS, in pentobarbital anaesthetized rats. Effects on incapacitation, oedema, neutrophil recruitment and kallikrein system activation, in the knee joint, were assessed.


RESULTS
MEN16132 and dexamethasone (10-300µg per knee) dose-dependently reduced carrageenan-induced joint pain, oedema and neutrophil infiltration, reaching a maximal inhibition of about 50%. Dexketoprofen exerted a similar analgesic activity, whereas it did not affect the other inflammatory responses. MEN16132 showed a partial inhibition of LPS-induced joint pain, whereas dexamethasone produced a full analgesic effect. Combination of MEN16132 and dexamethasone showed a strong synergistic interaction in inhibiting both carrageenan and LPS-induced knee joint inflammation. Dexamethasone did not prevent the contact activation of prekallikrein by carrageenan and the subsequent release of kallikreins and bradykinin in the synovium.


CONCLUSIONS
Steroids and kinin B(2) receptor antagonists appear to relieve arthritic symptoms induced by carrageenan or LPS and act synergistically to inhibit joint inflammation. This could have interesting therapeutic implications, possibly opening the way for combination therapies in the control of inflammatory arthropathies.
Valenti
C
C
Department of Pharmacology, Menarini Ricerche S.p.A., Florence, Italy.
Giuliani
S
S
Cialdai
C
C
Tramontana
M
M
Maggi
C A
CA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D001920:Bradykinin / Q000378:metabolism; D065094:Bradykinin B2 Receptor Antagonists; D002351:Carrageenan; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D007270:Injections, Intra-Articular; D007610:Kallikreins / Q000097:blood; D007719:Knee Joint; D008070:Lipopolysaccharides; D008297:Male; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*
C506838:(4-amino-5-(4-(4-(2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido)tetrahydro-2H-4-pyranoylcarbonyl)piperazino)-5-oxopentyl)(trimethyl)ammonium; D000894:Anti-Inflammatory Agents, Non-Steroidal; D065094:Bradykinin B2 Receptor Antagonists; D008070:Lipopolysaccharides; D043782:Receptor, Bradykinin B2; D013449:Sulfonamides; D003907:Dexamethasone; D002351:Carrageenan; D009952:Ornithine; D009195:Peroxidase; D007610:Kallikreins; D001920:Bradykinin