The roles of anti-arthritic gold(I)-thiolate drugs such as disodium aurothiomalate ('Myocrisin') in the modulation or promotion of oxygen radical-mediated oxidative damage in vivo are reviewed. In particular, the precise molecular mechanisms by which these novel second-line agents exert their therapeutic effects are discussed in terms of (i) the direct and indirect control of enzymes involved in the generation or scavenging of reactive oxygen species (ROS) such as superoxide ion, hydrogen peroxide and hydroxyl radical, (ii) the protection of proteins and relevant enzyme systems against attack by ROS and (iii) their direct involvement in the production (at appropriate 'target' sites) or scavenging of ROS in vivo. In addition, the role of the orally-effective gold(I)-phosphine complex auranofin in the control of oxidative damage in rheumatoid arthritis is also discussed.
SUMMARY It is postulated that the mobile inflamed joint may be subject to cyclical ischaemic reperfusion injury. Xanthine oxidoreductase is an enzyme thought to contribute to oxidative reperfusion injury, and the detection of this activity in human synovium is described. Three normal and five rheumatoid tissues were assayed with a carbon-14 radioassay detecting the conversion of [14C]xanthine to [14C]uric acid. Rheumatoid synovia contained 067-305 ,uU/g tissue (n=5), while normal synovia contained 1-2-5-0 ,uU/g tissue (n=3).Key words: reperfusion, ischaemia, ischaemic reperfusion, xanthine oxidase, xanthine, rheumatoid arthritis.We have previously suggested a mechanism involving ischaemic reperfusion injury to account for the unusual persistence of synovial inflammation.' This involved synovial ischaemia induced by exercise and reperfusion injury occurring on resting. In resting inflamed joints with an effusion, intra-articular pressures are raised compared with those of normal joints, but during exercise the pressure in these joints increases further.2 Lund-Olsen showed that partial pressures of oxygen (Po2) in the synovial fluid are lower in rheumatoid joints than in osteoarthritic or traumatised joints and fall during exercise.3 It is probable that, as the pressures measured during exercise often exceed the capillary perfusion pressure and indeed are greater than systolic blood pressure,24 occlusion of the vessels supplying the synovium occurs, explaining the drop in synovial fluid Po2. Once exercise has ceased intra-articular pressures drop and Po2 levels rise, often above basal levels, consistent, not only with reflow through the synovial vascular bed, but with a reactive hyperaemia.In many tissues much of the damage resulting from an ischaemic incident has been attributed to the postischaemic reperfusion phase,5 the ischaemic phase 'priming' the cells for the destructive activity occurring in the reperfusion phase. During temporary ischaemia low oxygen concentrations halt mitochondrial oxidative phosphorylation, and cellu-
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