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Titolo:
Rofecoxib [Vioxx, MK-0966; 4-(4 '-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: A potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles
Autore:
Chan, CC; Boyce, S; Brideau, C; Charleson, S; Cromlish, W; Ethier, D; Evans, J; Ford-Hutchinson, AW; Forrest, MJ; Gauthier, JY; Gordon, R; Gresser, M; Guay, J; Kargman, S; Kennedy, B; Leblanc, Y; Leger, S; Mancini, J; ONeill, GP; Ouellet, M; Patrick, D; Percival, MD; Perrier, H; Prasit, P; Rodger, I; Tagari, P; Therien, M; Vickers, P; Visco, D; Wang, Z; Webb, J; Wong, E; Xu, LJ; Young, RN; Zamboni, R; Riendeau, D;
Indirizzi:
Merck Frosst Ctr Therapeut Res, Dept Pharmacol, Kirkland, PQ, Canada MerckFrosst Ctr Therapeut Res Kirkland PQ Canada , Kirkland, PQ, Canada Merck Frosst Ctr Therapeut Res, Dept Biochem & Mol Biol, Kirkland, PQ, Canada Merck Frosst Ctr Therapeut Res Kirkland PQ Canada , Kirkland, PQ, Canada Merck Frosst Ctr Therapeut Res, Dept Med Chem, Kirkland, PQ, Canada Merck Frosst Ctr Therapeut Res Kirkland PQ Canada , Kirkland, PQ, Canada Merck Res Labs, Dept Pharmacol, Rahway, NJ USA Merck Res Labs Rahway NJ USA ck Res Labs, Dept Pharmacol, Rahway, NJ USA Merck Res Labs, Safety Assessment, W Point, PA USA Merck Res Labs W PointPA USA s Labs, Safety Assessment, W Point, PA USA
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 2, volume: 290, anno: 1999,
pagine: 551 - 560
SICI:
0022-3565(199908)290:2<551:R[M4'>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
NONSTEROIDAL ANTIINFLAMMATORY DRUGS; PROSTAGLANDIN G/H SYNTHASE-1; SELECTIVE-INHIBITION; COX-2 INHIBITORS; INFLAMMATION; ARTHRITIS; MECHANISM; ASSAYS; CELLS; PLATELETS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
39
Recensione:
Indirizzi per estratti:
Indirizzo: Chan, CC Merck Frosst Canada Inc, Merck Frosst Ctr Therapeut Res, Dept Pharmacol, POB 1005, Pointe Claire, PQ H9R 4P8, Canada Merck Frosst Canada IncPOB 1005 Pointe Claire PQ Canada H9R 4P8
Citazione:
C.C. Chan et al., "Rofecoxib [Vioxx, MK-0966; 4-(4 '-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: A potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles", J PHARM EXP, 290(2), 1999, pp. 551-560

Abstract

The discoveries that cyclooxygenase (COX)-2 is an inducible form of COX involved in inflammation and that COX-1 is the major isoform responsible for the production of prostaglandins (PGs) in the gastrointestinal tract have provided a rationale for the development of specific COX-2 inhibitors as a new class of anti-inflammatory agents with improved gastrointestinal tolerability. In the present study, the preclinical pharmacological and biochemical profiles of rofecoxib [Vioxx, also known as MK-0966, 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone], an orally active COX-2 inhibitor, are described. Rofecoxib is a potent inhibitor of the COX-2-dependent production of PGE(2) in human osteosarcoma cells (IC50 = 26 +/- 10 nM) and Chinese hamster ovary cells expressing human COX-2 (IC50 = 18 +/- 7 nM) with a 1000-fold selectivity for the inhibition of COX-2 compared with the inhibition of COX-1 activity (IC50 > 50 mu M in U937 cells and IC50 > 15 mu M in Chinese hamster ovary cells expressing human COX-1). Rofecoxib is a time-dependent inhibitor of purified human recombinant COX-2 (IC50 = 0.34 mu M) but causedinhibition of purified human COX-1 in a non-time-dependent manner that could only be observed at a very low substrate concentration (IC50 = 26 mu M at 0.1 mu M arachidonic acid concentration). In an in vitro human whole blood assay, rofecoxib selectively inhibited lipopolysaccharide-induced, COX-2-derived PGE(2) synthesis with an IC50 value of 0.53 +/- 0.02 mu M compared with an IC50 value of 18.8 +/- 0.9 mu M for the inhibition of COX-1-derivedthromboxane B-2 synthesis after blood coagulation. Using the ratio of the COX-1 IC50 values over the COX-2 IC50 values in the human whole blood assay, selectivity ratios for the inhibition of COX-2 of 36, 6.6, 2, 3, and 0.4 were obtained far rofecoxib, celecoxib, meloxicam, diclofenac, and indomethacin, respectively. In several in vivo rodent models, rofecoxib is a potentinhibitor of carrageenan-induced paw edema (ID50 = 1.5 mg/kg), carrageenan-induced paw hyperalgesia (ID50 = 1.0 mg/kg), lipopolysaccharide-induced pyresis (ID50 = 0.24 mg/kg), and adjuvant-induced arthritis (ID50 = 0.74 mg/kg/day). Rofecoxib also has a protective effect on adjuvant-induced destruction of cartilage and bone structures in rats. In a Cr-51 excretion assay for detection of gastrointestinal integrity in either rats or squirrel monkeys, rofecoxib has no effect at doses up to 200 mg/kg/day for 5 days. Rofecoxib is a novel COX-2 inhibitor with a biochemical and pharmacological profile clearly distinct from that of current nonsteroidal anti-inflammatory drugs and represents a new therapeutic class of anti-inflammatory agents for the treatment of the symptoms of osteoarthritis and rheumatoid arthritis withimproved gastrointestinal tolerability.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 11/07/20 alle ore 20:08:59