Clinical and bio-inorganic studies on anti-arthritic gold complexes

The discovery that gold compounds are beneficial in the treatment of rheumatoid arthritis is possibly the greatest breakthrough in the management of this devastating crippling disease which we will witness in this century. This thesis describes my clinical and research experience with gold compounds over the past seven years and also contains my attempts to understand some of the clinical, chemical and biological actions of the anti- arthritic gold complexes, in the hope that my observations may prove beneficial to the management of patients with rheumatoid arthritis. Chapter I and II describe the history of gold in medicine and its subsequent use as an agent in the treatment of rheumatoid disease. Gold's presumed magical qualities and its resemblance to the "essence" of the sun made it a natural choice as a healing agent by priests and shamen. Gold therapy results in toxicity in at least 30% of patients. It was to identify some of these risk that I engaged in the clinical studies reported in chapters III, IV and V. My findings indicated that side-effects such as rash, mouth ulcer and proteinuria had predictable patterns of development, all predominantly occurring within the first year, whereas thrombocytopenia and low white blood cell count could appear at any time. No predictive correlates could be established for patients who had gone into sustained remission, but the data strongly suggested that patients who improve within six months may continue gold therapy for up to three years with an increasing margin of safety for mucocutaneous and renal toxicity. Finally, in Chapter VIII my observations that gold sodium thiomalate inhibits the serine esterase thrombin in vitro and in vivo is described. Gold sodium thiomalate inhibits the action of thrombin on washed human platelets and the thrombin clotting time of platelet rich plasma and platelet poor plasma. Using an experimental model of experimentally induced thrombosis it was shown that rabbits treated with pharmacological concentrations of gold sodium thiomalate had significantly reduced thrombus weight compared to controls. Gold sodium thiomalate had no effect on fibrinolysis nor platelet survival, therefore the reduction in thrombus weight was most likely due to the direct inhibition of the thrombin as was observed in vitro. Clearly such a finding could have far reaching consequences in the treatment of vasculitis, lupus glomerulonephritis, coronary artery disease and cerebro-vascular disease. (Abstract shortened by ProQuest.)