A well established model of arthritis induced in rabbit knee joints by immobilisation in full extension for 30 days was used to evaluate the in vivo effects of 2-5, 5-0, and 10-0 mg/kg body weight of tiaprofenic acid on articular cartilage proteoglycans. The drug was given subcutaneously every 24 hours during the entire immobilisation period. Immobilised animals not treated with drugs and normal animals were used as controls. In the non-drug treated immobilised animals articular cartilage showed evidence of surface damage accompanied by synovial hypertrophy and effusion. Proteoglycan concentrations were reduced in cartilages of these joints and the incorporation of 35SO24 into macromolecular proteoglycans was higher than in cartilages of non-immobilised controls. Gel filtration chromatographic studies of both resident and 35S labelled proteoglycans isolated from immobilised joint cartilage showed reduced aggregation and the presence of degraded proteoglycan subunit species. Whereas the administration of 10,0 mg/kg tiaprofenic acid every 24 hours to immobilised animals exacerbated the degradation and loss of proteoglycans from joint cartilages, 5-0 mg/kg tiaprofenic acid provided some protection of these macromolecules, as shown by the concentrations and extractability of proteoglycans from cartilages, which were comparable with those from non-immobilised controls. A high incorporation of 35S into proteoglycans was demonstrated, together with reduced catabolism of proteoglycans, indicating preservation of chondrocyte anabolic activity. At a tiaprofenic acid dose of 2.5 mg/kg, however, no beneficial effects on cartilage proteoglycans could be shown.
In a previous study, tiaprofenic acid (TA) was administered daily over a 30-day period at 5 and 10 mg/kg of body weight subcutaneously (s.c.) to animals with arthritis induced by immobilisation. The 10 mg/kg dose exacerbated the loss of proteoglycan from joint cartilage but the 5 mg/kg dose showed protective effects on articular cartilage. These results led us to investigate the concentration of TA achieved in synovial fluid of both the immobilised and non-immobilised rabbit joints after single s.c. doses of 5 or 10 mg/kg. The half-lives of elimination of TA from the synovial fluids of the immobilised joints were 1.27 and 1.07 h after the 5 and 10 mg doses, respectively, and 0.66 and 0.39 h in the non-immobilised contralateral joints. Clearances from synovial fluid to plasma were found to be 0.41 and 0.55 ml/h/kg from the immobilised joints after the 5 and 10 mg doses, respectively, and 0.11 and 0.25 ml/h/kg from the non-immobilised contralateral joints. The peak concentration of TA achieved in synovial fluid of immobilised knee joints after a single s.c. injection of 10 mg/kg was approximately two times greater than the concentrations achieved after administration of 5 mg/kg by the same route and two to six times greater than the levels achieved after oral administration of TA at 600 mg/day in humans.
This study compares the effects of two non-steroidal anti-inflammatory drugs, Bufferin A (BA) and L-5409709 (L-54), on nociceptive behaviour and spinal Fos expression induced by subcutaneous formalin in the rat. BA contains aspirin. L-54 contains ibuprofen, caffeine and paracetamol. Doses based on the human posology were administered orally 30 or 40 min before subcutaneous intraplantar injection of formalin (1.5%, 50 microl) in the right hindpaw. Low doses (BA, 24 mg/kg; L-54, 21.5 mg/kg) did not significantly affect the behavioural pain response. High doses (BA, 480 mg/kg; L-54, 430 mg/kg) reduced the late phase of the response by 42% and 62% respectively, but did not affect the early phase of the response. No sedative side-effects were observed. The two drugs had different effects on the number of spinal Fos-like immunoreactive neurones 2 h after the formalin injection. Fos expression was reduced after BA treatment, and this reduction was correlated to and matched the reduction of the pain response. In contrast, Fos expression after L-54 treatment was not reduced and was not correlated to the reduction in the pain response. The Fos results reveal clear differences in the way that BA (aspirin) and L-54 (ibuprofen + caffeine + paracetamol) affected transmission of the noxious signal. They suggest that BA did not act beyond the spinal cord and that L-54 had more central sites of action than BA.
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