title: Effect of Intra-articular 4-(S)-amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl} piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride (MEN16132), a kinin B2 receptor antagonist, on nociceptive response in monosodium iodoacetate-induced experimental osteoarthritis in rats.
abstract: The present study was designed to investigate the role of bradykinin (BK) in the knee joint osteoarthritis induced by intra-articular (i.ar.) administration of monosodium iodoacetate (MIA) in the rat, and to determine the efficacy of the kinin B(2) receptor antagonists, 4-(S)-amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl} piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride (MEN16132) and icatibant, in reducing pain. Rats received MIA (1 mg/25 microl i.ar.) in the right knee. MEN16132, icatibant (1, 3, and 10 microg/25 microl i.ar.), or saline were administered 7 days after MIA treatment, and their antinociceptive effect was observed for 2 weeks. MEN16132 induced a marked and sustained reduction of incapacitation produced by MIA, approximately 56% inhibition of pain at 3 microg/knee. MEN16132 analgesia was more potent and longer lasting, up to 10 days, than icatibant. MEN16132 (3 microg/knee), at different time points from MIA treatment in separate groups of animals, produced comparable maximal antinociceptive effects, whereas the pain response induced by MIA was unaffected if MEN16132 (10 microg/knee) was administered in the contralateral knee. Indomethacin at high doses (100-625 microg/knee) inhibited by approximately 40% but with a short duration the MIA-induced pain. MIA treatment produced a significant increase of BK and prostaglandin E(2) (PGE(2)) metabolite levels in synovial fluid up to 21 days, and PGE(2) metabolite levels were reduced almost to basal values by MEN16132. In conclusion the potent and long-lasting analgesic effect of MEN16132 in MIA-induced osteoarthritis indicates an important role for BK in osteoarthritic pain, and suggests that MEN16132 can be a candidate for the treatment of this chronic disease.
authors.affiliation: Pharmacology Department, Menarini Ricerche S.p.A., via Rismondo 12A, I-50131, Florence, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Cialdai
authors.forename: Sandro
authors.initials: S
authors.lastname: Giuliani
authors.forename: Claudio
authors.initials: C
authors.lastname: Valenti
authors.forename: Manuela
authors.initials: M
authors.lastname: Tramontana
authors.forename: Carlo Alberto
authors.initials: CA
authors.lastname: Maggi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use; D065094:Bradykinin B2 Receptor Antagonists; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006614:Hindlimb / Q000503:physiopathology; D007270:Injections, Intra-Articular; D007461:Iodoacetates; D008297:Male; D009952:Ornithine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010003:Osteoarthritis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D013582:Synovial Fluid / Q000378:metabolism
chemical_list: 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; D007461:Iodoacetates; D013449:Sulfonamides; C065679:icatibant; D009952:Ornithine; D015232:Dinoprostone; D001920:Bradykinin