Chrysotherapy

The earliest use of gold complexes in medicine primarily involved gold thiolates, which being yellow or even gold-colored in solution, led to their designation as chrysotherapy (chrysos is Greek for gold). 

Gold(I) thiolates in the thiolate gold ratio of 1 1 or 2 1 were the first chrysother-apeutic agents to be used. They are administered intramuscularly and not orally because they cannot be readily absorbed from the gut and by other tissues. Table 6.1 lists some chrysotherapy agents that will be discussed, with their formulae and Figure 6.1 shows chemical structures for some important thiolate ligands. 

Table 6.1 Medicinally important chrysotherapy complexes. Adapted from Shaw [17].

This type of in vitro study is relevant because it mimics likely physiological conditions. Red cells contain 1-2 mM GSH so the formation of glutathione complexes would be a likely consequence when auranofin metabolites enter red cells [112, 113]. Compared with typical in vivo gold concentrations of 10-15 pM observed in patients, the Ki values for the four gold complexes are less than anticipated. This indicates that chrysotherapy can greatly depress GSH-Pxase activity in vivo so the normal cellular redox balance would be displaced, favoring the accumulation of H2O2 and possibly GSH [3, 79, 114]. 

Reglinski, J., Hoey, S. and Smith, W.E. (1988) Exchange reactions between disulfides and myocrisin an in vitro model for a mechanism in chrysotherapy. Inorganica Chimica Acta, 152, 261—264. 

Shaw, C.E. Ill (1979) The mammalian biochemistry of gold an inorganic perspective of chrysotherapy Inorganic Perspective in Biolc and Medicine, 2, 287-355. 

Cottrill, S.M., Sharma, H.L, Dyson, D.B., Parish, R.V. and McAuliffe, C.A. (1989) The role of the ligand in chrysotherapy a kinetic study of gold-199- and sulfur-35-labeled myocrisin and auranofin. Journal of the Chemical Society, Perkin Transactions II, (1), 53-58. 

G12. Gottlieb, N. L., Smith, P. M., and Smith, E. M., Tissue gold concentration in a rheumatoid arthritic receiving chrysotherapy. Arthritis Rheum. 15, 16-22 (1972). 

L13. Lorber, A., Cohen, R. L., Chang, C. C., and Anderson, H. E., Gold determination in biological fluids by atomic absorption spectrophotometry application to chrysotherapy in rheumatoid arthritis patients. Arthritia Rheum. II, 170-177... 

P9. Pole, D. J., Balazs, D. H., and Maserai, J., Plasma gold estimations in patients receiving chrysotherapy for rheumatoid arthritis. Med. J. Aust. U, 1181-1183 (1971). 

The Mammalian Biochemistry of Gold An Inorganic Perspective of Chrysotherapy 11... 

The complexes which have been used in chrysotherapy (the treatment of rheumatoid arthritis by gold drugs) are given in Table 9. Of these, (11), (12) and (18) are the most important. Complexes (11) and (12) were for many years dominant, but they must be administered parenterally, and the new drug (18) is unique in that it is therapeutically beneficial when administered orally.9-14 240... 

The biochemistry and medicinal chemistry of the gold(I) thiolates used in chrysotherapy have been thoroughly reviewed elsewhere9"14,240 and this account will deal only with stability and ligand exchange reactions of the gold(I) thiolates of interest to coordination chemists. 

The complexes sodium aurothiomalate and sodium aurothioglucose provide effective therapy for rheumatoid arthritis but can produce unpleasant and toxic reactions because of the relatively large doses used (up to 250jumol (50 mg) per week). The resultant high concentrations of Au in plasma of patients receiving chrysotherapy may be measured easily by solvent extraction and FAAS. The main advantages of ETA—AAS are the direct analysis and the sensitivity to measure the various Au containing species in body fluids. 

In vivo studies indicate that gold-based chrysotherapy agents are prodrugs, species that undergo transformation after administration to form the active species. The metabohsm... 

After attempts with chrysotherapy and lobenzarit, a 24-year-old woman was given bucillamine 300 mg/day and a glucocorticoid, predonine, for rheumatoid arthritis. After 10 months she noticed bilateral breast... 

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