Evaluation of pharmacological profile of meloxicam as an anti-inflammatory agent, with particular reference to its relative selectivity for cyclooxygenase-2 over cyclooxygenase-1.
We studied the anti-inflammatory activity of meloxicam on rat carrageenin-induced pleurisy and its toxicity for rat gastric mucosa, relative to its in vitro inhibitory potency against partially purified cyclooxygenase (COX)-1 and COX-2 preparations in order to clarify the pharmacological profile of the compound as an anti-inflammatory agent. In rat carrageenin-induced pleurisy, the plasma exudation rate peaked at 5 h, at which time COX-2 was detectable in cells from the pleural exudate. Meloxicam and piroxicam (1 and 3 mg/kg) and NS-398 (3 mg/kg) showed almost equal anti-inflammatory potency against 5-hour pleurisy. A single oral administration of the compounds caused a dose-dependent increase in the number of rats with gastric mucosal erosion. The ED50 value for meloxicam (5.92 mg/kg) was significantly higher than that for piroxicam (1.76 mg/kg), indicating that meloxicam is safer. Indometacin showed intermediate safety (2.59 mg/kg). In in vitro experiments, indometacin inhibited COX-1 about 1.7 times more potently than COX-2. NS-398 inhibited COX-2 with an IC50 of 0.32 microM, but never affected COX-1 activity, even at 100 microM. In the same assay system, meloxicam inhibited COX-2 about 12 times more selectively than COX-1. Piroxicam, however, inhibited both isoforms almost equally. These results indicate that meloxicam is a potent anti-inflammatory agent with low gastric toxicity. One reason for its in vivo pharmacological profile may be related to its relative selectivity for COX-2 over COX-1. Thus, meloxicam may belong to a group of COX-2 selective anti-inflammatory agents with a better safety profile than conventional COX-1 and COX-2 nonselective anti-inflammatory agents.
Ogino
K
K
Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Japan.
Hatanaka
K
K
Kawamura
M
M
Katori
M
M
Harada
Y
Y
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D002351:Carrageenan / Q000008:administration & dosage; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology / Q000633:toxicity; D007527:Isoenzymes / Q000302:isolation & purification / Q000378:metabolism*; D008297:Male; D000077239:Meloxicam; D008565:Membrane Proteins; D009578:Nitrobenzenes / Q000494:pharmacology / Q000633:toxicity; D010894:Piroxicam / Q000494:pharmacology / Q000633:toxicity; D010998:Pleurisy / Q000139:chemically induced / Q000188:drug therapy; D011451:Prostaglandin-Endoperoxide Synthases / Q000302:isolation & purification / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology / Q000633:toxicity; D013810:Therapeutic Equivalency; D013843:Thiazines / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; D013843:Thiazines; D013844:Thiazoles; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D010894:Piroxicam; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D000077239:Meloxicam; D007213:Indomethacin