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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.

The presence of the xanthine oxidase enzyme system has been demonstrated in the rheumatoid synovium. This supplies a reactive oxygen species generating system to synovium that is subjected to hypoxic-reperfusion cycles (cf inflamed rheumatoid synovium). An antibody to bovine milk xanthine oxidase has been used to localise the enzyme by immunohistochemistry to synovial endothelium. This implicates the endothelial cell as playing a major part in exacerbations of synovitis, induced by radicals.

Objective-To apply an electron spin resonance (ESR) spectroscopic technique as a means of determinKing the oxidising capacity of reactive oxygen species produced during hypoxia and reoxygenation of diseased human synovial tissue. Methods-Twenty four specimens of fresh synovial tissue were obtained from patients undergoing primary total knee joint replacement and graded according to the degree of inflammation present.Tissue samples were subjected to an ex vivo hypoxia-reoxygenation cycle in the presence of the nitroso based spin trap, 3,5-dibromo-4-nitrosobenzene sulphonate. The degree of oxidation of the spin trap to a stable free radical was determined and folilowed with time. Control samples were subjected to hypoxia only. Results-The results indicate that the oxidising capacity of reactive oxygen species produced by human synovial tissue varies with the degree of inflammation present. Only the more inflamed specimens, from both rheumatoid arthritis and osteoarthritis patients, demonstrated increased production of reactive oxygen species when subjected to a hypoxia-reoxygenation cycle. This change was reduced by both Mason'6 have similarly assigned the three line spectrum generated in such experiments to an oxidation product of DBNBS. In accordance with this assignment, the ESR signal is abolished by reduction with ascorbic acid. '7 In the present study, immunohistochemical analysis was also performed to examine potential relationships between the clinical scoring system used (based on thickness and colour of the synovium), histological features, and the oxidising capacity of reactive oxygen species produced by the synovial tissue specimens following hypoxia-reoxygenation.In view of the potential critical importance of the enzyme xanthine oxidase/dehydrogenase to the process of hypoxic-reperfusion and its localisation to the synovial endothelium,8 we chose to stain our sections in order to identify the vascular endothelium and allow an assessment of vessel density.In addition, using this method we have assessed the capacity of oxypurinol (a competitive inhibitor of xanthine oxidase)'8 and amflutizole (a non-competitive inhibitor),'9 to limit the generation of synovial tissue derived oxidising species following ex vivo hypoxia-reoxygenation.Patients and methods This study was approved by the London Hospital Medical College Ethical Committee.Patients from whom samples were obtained were all undergoing primary total knee joint replacements at the Royal London Hospital. Of the 24 patients studied (age range 48-82), 15 had primary osteoarthritis and nine had rheumatoid arthritis, as diagnosed by the referring physician. Samples of tissue were obtained from the suprapatellar and fat pad regions of the knee joint at surgery. The tourniquet used for the prevention of operative blood loss had been applied for an average of 11 (SD 6) minutes before sample collection. Time from sampling to commencement of the experimental protocol was approximately 30 minutes. The tissue samples were graded clinically as bein...

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