Effects of tiaprofenic acid (Surgam) on cartilage proteoglycans in the rabbit joint immobilisation model.

Abstract

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.

Pharmacokinetics of tiaprofenic acid in normal rabbits and rabbits subjected to joint immobilisation

“…Thus, Rainsford et al [24] found greater radioactivity in the carrageenan-inflamed paws of rats after the administration of several radiolabelled non-steroidal anti-inflammatory drugs. Although the arthritic model used by Rainsford et al [24] differs markedly from that used in the present study, synovial effusion and joint inflammation occurred in our model [7]. One of the aims of the present study was to identify the causes of the biochemical changes provoked in the immobilised knee articular cartilage after the 10 mg/kg dose of TA.…”

“…IL-1 has been shown to suppress proteoglycan synthesis and increase proteoglycan resorption in cartilage in vitro [28]. We have proposed [7] that the elevation of IL-t in cartilage of animals treated with 10 mg/kg could be responsible for the exacerbation of proteoglycan loss from cartilage of the immobilised joints when the drug was administered at this high dose [7].…”

“…It has potent anti-inflammatory and analgesic properties [1][2][3] and has demonstrated efficacy in double blind clinical trials for both inflammatory arthritis [4] and osteoarthritis [5,6]. In a previous study, using an animaI model of arthritis induced by immobilisation [7], we demonstrated a dose-related response of articular cartilage proteoglycan levels to TA. When administered prophylactically at 5 mg/kg, but not 2.5 mg/kg, TA prevented the loss of proteoglycans from articular cartilage.…”

“…Left knee joints of 46 animals were immobilised for 12 days and 18 non-immobilised rabbits were used a controls. Joint immobilisation was achieved usinl two plastic splints (220 x 25 x 2 mm; 200 x 2~ x 2 mm) as described previo~asly [7]. The rabbit were allowed to move freely in cages (580mn x depth 482 mmx height 365 ram) during the im mobilisation period.…”

“…The model of joint arthropathy used was initially described by Langenski61d et al [11] and modified by Meyer-Carrive and Ghosh [7]. The animals were 64 mature (9-12) months old) rabbits of the New Zealand White strain weighing 3-5 kg.…”