Effects of the NSAIDs meloxicam and indomethacin on cartilage proteoglycan synthesis and joint responses to calcium pyrophosphate crystals in dogs.
NSAIDs are a major cause for concern for their propensity to cause joint deterioration in canine, as in human, patients receiving these drugs for treatment of pain in osteoarthritis and other acute and chronic painful conditions. To determine the potential effects of the new NSAID meloxicam on cartilage integrity, the effects of this drug on proteoglycan biosynthesis in vitro and ex vivo were compared with those of indomethacin, a known inhibitor of sulphated proteoglycans that accelerates joint injury in human osteoarthritis. In vitro cartilage proteoglycan synthesis from a radiosulphate precursor was unaffected by 0.5-10.0 micromol/L meloxicam but was significantly inhibited by 50 micromol/L indomethacin after 6 or 24 h incubation of femoral or tibial cartilage explants in organ culture. This is in accord with previous observations in human or porcine articular cartilage under the same culture conditions. Studies were performed in vivo to establish the effects of the NSAIDs on joint integrity. This involved determining cartilage proteoglycan synthesis ex vivo, leukocyte, fluid and protein accumulation, as well as pain relief. Thus, meloxicam (0.2 mg/kg i.v. x 3 doses) or indomethacin (0.5 mg/kg i.v. x 3 doses) was given for 26 h and the effects were compared with a control (1.0 ml saline i.v. x 3 doses) in dogs in which acute inflammation had been induced by intra-articular (i.a.) injection of calcium pyrophosphate dihydrate (CPPD) crystals into the right stifle joint, an equivalent volume of saline being injected into the left stifle joint as a control. No effects were observed of the treatment with the NSAIDs on ex vivo sulphated proteoglycan synthesis. The lack of the expected inhibitory effects of indomethacin may be related to the relatively low plasma concentrations of this drug obtained during the 26 h period of treatment. The pain response, which was elicited up to 6 h following i.a. injection of CPPD crystals, was totally prevented by the treatment with meloxicam and to a lesser extent with indomethacin. There were no effects from the drug treatment on synovial inflammatory reactions (fluid and cell accumulation), although the protein concentration of the exudate was reduced by meloxicam. This indicates that, at the doses given, it was possible to discriminate the analgesic action from the anti-inflammatory action of the two NSAIDs, this being achieved at relatively low plasma concentrations of these drugs. In conclusion, while relatively high therapeutic concentrations of indomethacin inhibit cartilage proteoglycan synthesis, this is not an effect seen even at high concentrations of meloxicam. Furthermore, the lack of effects on proteoglycan synthesis was evident when these two drugs were given in vivo to dogs. However, the signs of pain, but not the inflammation in the joint, were relieved by low plasma concentrations of the drugs. Meloxicam may thus be safely employed for acute analgesia without the potential risks of joint cartilage damage that occurs with indomethacin given at antiinflammatory doses for long periods of time.
Rainsford
K D
KD
Division of Biomedical Sciences, School of Science and Mathematics, Sheffield Hallam University, Sheffield, UK.
Skerry
T M
TM
Chindemi
P
P
Delaney
K
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001168:Arthritis / Q000139:chemically induced / Q000378:metabolism / Q000662:veterinary; D002131:Calcium Pyrophosphate / Q000378:metabolism*; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism*; D003460:Crystallization; D004283:Dog Diseases / Q000139:chemically induced / Q000378:metabolism; D004285:Dogs / Q000378:metabolism*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D007596:Joints / Q000187:drug effects*; D000077239:Meloxicam; D011509:Proteoglycans / Q000096:biosynthesis*; D013585:Synovitis / Q000139:chemically induced / Q000378:metabolism / Q000662:veterinary; D013843:Thiazines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011509:Proteoglycans; D013843:Thiazines; D013844:Thiazoles; D000077239:Meloxicam; D002131:Calcium Pyrophosphate; D007213:Indomethacin