Pharmacology and toxicology of heavy metals: Gold

Phannac. Ther. A. Vol. I, pp. 119-125, 1976. Pergamon Press.

Printed in Great Britain

Specialist Subject Editor: W. G. LEVINE

P H A R M A C O L O G Y AND TOXICOLOGY OF H E A V Y METALS: GOLD HAROLD G. PETERING Department o[ Environmental Health, Universityof Cincinnati Collegeo[Medicine, Cincinnati, Ohio, USA

LIKE silver, gold has been known and used by man for thousands of years. It is mentioned many times in the early books of the Old Testament (e.g. Gen. 2 : 11; Gen. 13 : 2; Ex. 25 : 11), and was used as a decorative metal by the ancient Egyptians prior to 3400 ac. The gold used in these early periods was placer gold, obtained by washing sand or gravel, and was made into jewelry or other articles by hammering (Rickard, 1932). The early method of recovering alluvial gold particles from sand by the use of animals skins is believed to have been the inspiration of the story of Jason and the golden fleece (Hoover and Hoover, 1950). The melting of gold as a means of its recovery and its use in the manufacture of articles was accomplished about 3000 BC (Hoover and Hoover, 1950). Apart from its value as a precious metal for jewelry and as a monetary standard, gold is used in the manufacture of selected delicate instruments, and has some application in art and photography. Gold is found throughout the world in relatively pure form in lodes and placer deposits, as well as in impure form in many base metal ores, particularly in deposits of copper and silver. It is recovered as a by-product of the isolation of magnesium and bromine from sea water. Jones (1970) has recently published an extensive review of the gold content of water, plants, and animals. Although the number of samples in this study was not great, some estimate of environmental distribution of gold can be made from the report. Sea water and fresh ground waters contain the element in the range of 0.001-44.0 ng/l. Using neutron-activation analysis, Jones gave a mean value of 0.05 ng/l for the concentration in sea water. Plant ash has an average of 7 mg/kg and a maximum value of 36 mg/kg which is much greater than that found in the earth's crust. These data suggest that gold is concentrated by plants, but there are no data on the possibility of concentration of gold in land or marine animals. It may well be that there is a source of gold for plants not derived from the soil in which they are grown. One such source may be the fly ash from incinerators and power plants, since the Bureau of Mines has shown that levels of gold in fly ash over metropolitan Washington, D.C. is in the range of 0.02-0.05 oz/ton, or about 1.5 mg/kg. Gold has found its way into medical practice through the observations of Robert Koch, who, in the late nineteenth century, showed that low concentrations of gold salts adversely affected the tubercle bacillus. Gold salts were thereafter used sporadically to treat tuberculosis and syphilis without much success. However, during this time gold compounds were also used to treat arthritis and lupus erythematosus, which at that time were thought to be due to the tubercle bacillus (Goodman and Gilman, 1965). In 1929, Forestier published a report on gold therapy for rheumatoid arthritis which is considered to be the basis for present interest in this subject. Gold compounds are still an important group of drugs in the armamentarium of the rheumatologist, as is evident from the review of Freyberg (1966). Radioactive colloidal gold preparations are used to treat certain malignancies involving ascites, and they are also used as diagnostic tools in liver scanning. 1. CHEMISTRY AND ANALYTICAL METHODS Gold, copper, and silver constitute Group IB of the Periodic Table. Gold is a member of the third transition series, with the electronic configuration 5dt°6s t. It exists in the 119 JPTA Vol. 1, No. 2--A

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+ 1 and + 3 oxidation states; and as Au ~÷(d ~o)it forms linear and tetrahedral complexes with coordination numbers 2 and 4. As Au 3÷ (d s) it forms complexes with planar, trigonal, bipyramidal, and octahedral geometry, and with coordination numbers of 4, 5, and 6, respectively. Au I÷ is the common form of gold in the antiarthritic drugs, forming linear compounds with sulfur in most of these. The chemistry of gold in general is that of complex compounds; no simple gold cations exist in aqueous solution. There are a number of Au ~÷ complexes, but the most important ones are Au(CN)~, AuCl~, and Au(S203)~-. Aurous ion, Au ~+, has a strong affinity for SH groups or RS- radicals, while Au 3÷, the auric ion, for the most part forms complexes which are strong oxidizing agents. Gold can also form organometallic compounds (Armer and Schmidbaur, 1970), among which the most stable are the dialkyls with the formula R2AuX, where X is Cl-, Br-, CN-, SO~, etc. Phosphinogold alkyls where Au ~+ is involved and which have the formula R3PAuR' are known. These have recently been introduced as possible anti-arthritic drugs. Gold forms beautifully colored (red) colloidal sols when auric compounds are reduced to metallic gold; and some insoluble gold compounds, such as gold sulfide, also form colloidal sols. Sols made from l~Au compounds are the basis for localized radioisotope therapy for malignancies. Herz (1966) has reviewed the analytical chemistry of gold, as has Beamish (1961a and 1961b). Organic matter is removed by ashing and the metal in the residue can be dissolved in fresh aqua regia. Gold can then be reduced to the metallic form under conditions where it will be precipitated quantitatively, after which it is collected, washed, dried, and weighed. In carrying out this analytical procedure, it is necessary that gold be in solution as auric chloride with some excess of hydrochloric acid and free of nitrates or other oxidizing agents. It may then be reduced to metallic gold by such reducing agents as FeSO4, oxalic acid, SO2, or SO;. Washing the precipitate causes no loss and the precision of this procedure should be as good as that of any other gravimetric method. Titrimetric methods (Herz, 1966) depend on the reduction of Au 3÷ to Au ~÷ or Au ° in the presence of an excess of hydrochloric acid. Nitrates should be absent, of course, since they act as oxidizing agents. The reducing solution must be in slight excess for complete precipitation of gold, and the excess is back-titrated with standard permanganate solution. Equations covering the reduction are: Au 3÷ + 3 Fe 2÷ 2 Au 3++ 3 H2C204

) 3 Fe 3+ + Au ° ) 6 H ÷ + 6 CO2 + Au °.

An iodimetric method is also available in which Au 3÷ is reduced to Au '+ and the liberated iodine titrated with standard thiosulfate (Gooch, 1899) or arsenic trioxide (Kolthoff and Belcher, 1957). In the titrimetric methods, 1 ml of 0.01N permanganate is equivalent to 6.567 mg, and 1 ml of 0.01N thiosulfate solution is equivalent to 9.85 mg of gold. Thus one can see that with microtechnique one can detect microgram quantities of gold by these methods. Polarographic and photometric methods (Herz, 1966) for gold are also available, and these can be adapted to microanalytical procedures. As little as 50/zg of gold per ml can be detected by photometric methods when clear solutions of auric acid are reduced with SnC12 to the gold sol known as Cassius purple (Sandell, 1959). It would appear that the use of atomic absorption spectrophotometry offers the best and most rapid method for the detection of gold in tissue or other samples of biological origin when a sophisticated instrument equipped with a micro-sampling device is available. Recently, several Netherlands workers have presented evidence that this method is the one of choice to monitor the metabolic fate of gold compounds used in the treatment of arthritis (den Oudsten, 1969). 2. T H E R A P E U T I C USE AND PHARMACOLOGY OF GOLD COMPOUNDS The most important therapeutic use of gold compounds is in the treatment of chronic rheumatoid arthritis (except where irreversible bone changes have occurred) and lupus

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erythematosus. In the opinion of such rheumatologists as Freyberg (1966), chrysotherapy (use of gold compounds) is to be preferred over corticoids or ACTH, however; most physicians would use these drugs only as alternative therapy, following inadequate response and adverse patient reaction to the more usual agents. Two advantages to chrysotherapy should be notedmnamely, that gold compounds are not immunosuppressive, and that specific antidotes are available to treat toxic side effects when they occur (Lock;e, 1961; Sigler et al., 1963; Smith, 1963; Huge, 1969). However, toxicity occurs very frequently. A variety of agents is available for chrysotherapeutic use in rheumatoid arthritis. Among the most commonly used are the following: (a) Aurothioglucose USP (Solganol®). Its formula is C6H.OsSAu, and it contains about 50 per cent gold. It is water soluble but is usually used as an oil suspension for i.m. injection. (b) Gold Sodium Thiomalate USP and BP (Myochrysine®). Its formula is Na2C4H304SAu, and it contains about 50 per cent gold. It is used as an aqueous solution for either i.v. or i.m. injection. (c) Gold Sodium Thiosulfate N F (Sanochrysine ®, Crisalbine ®, or Sanocrysin®). Its formula is Na2Au(S203)2-2 H20, and it contains about 39 per cent gold. It is used as an aqueous solution for i.v. injection. (d) Aurothioglycoanilide (Lauron®). It is 2'-(auromercapto)-acetanilide whose formula is CsHsOSAu. It is not water soluble and is usually given in oil suspension for i.m. injection. The drug contains about 54 per cent gold. Recently a new agent has been reported which is active in experimental arthritis upon oral administration to animals (Walz et al., 1971). It is triethylphosphinogold chloride or (C2H~)3PAuCI (SKF 36914) and is said to have fewer side effects than parenteral preparations. This is the only drug among those now being used or studied which does not contain a sulfur atom. Gold (~Au) Solution N F is a radioactive gold sol for specific radiotherapy of malignancies, especially those involving ascites. It will not be discussed further, but additional information on its toxicity and use may be found in the U.S. Dispensatory (J. B. Lippincott Co., 1967), in Remington's Pharmaceutical Sciences (Mack Publishing Co., 1965), and in the U.S. Pharmacopeia (Mack Publishing Co., 1970). Although there are problems with side effects, dosage, and patient selection, in the hands of skilled rheumatologists, gold therapy appears to give excellent results in many cases. Goodman and Gilman (1965) and Freyberg (1966) offer extensive reviews of chrysotherapy which should be consulted, and Feruandez-Herlihy (1970) has recently presented a carefully detailed regimen for chrysotherapy; he considered gold sodium thiomalate as the drug of choice, but also indicated that aurothioglucose can provide effective therapy for arthritis. He has, in addition, specified a procedure for selecting patients, and he uses chrysotherapy as an adjunct to a "basic" maintenance program of rest, exercise, heat, and the use of acetylsalicylic acid. The rate of partial and complete remissions of arthritis with gold therapy varies from 57 per cent to 82 per cent, depending on the control of dosage, the drug used, and the manner of managing the toxic side effects. Huge (1969) in discussing his experience with 151 patients, pointed out that long term remissions (measured in years) were obtained in more than 50 per cent of his cases, with freedom from the use of other anti-arthritic drugs. Nevertheless, although the clinical usefulness of gold therapy has been established by several well-controlled studies carried out in Great Britian (Research Subcommittee of the Empire Rheumatism Council, 1960 and 1961), toxicity continues to be a problem for many patients. Freyberg (1966) has stated: 'All gold salts that may have therapeutic value have toxic potentialities. Unfortunately, there is no reliable method of predicting or testing to determine which persons will develop toxicity from gold as it is employed for the treatment of rheumatoid arthritis'. This is more or less true of every therapeutic agent used by the physician, and the problem resolves itself into understanding the toxic potentialities and their relationship to a specific form of gold, to the dosage schedule, and to the manner of early detection of toxicity and its

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treatment. Freyberg (1966) and Goodman and Gilman (1965) have outlined in great detail the toxic side effects which have been noted. Briefly they are: skin lesions (dermatitis and mouth lesions ranging from stomatitis to gingivitis); gastrointestinal disturbances such as nausea, anorexia, diarrhea, and very occasionally ulcerative enterocolitis; the so-called 'toxic nephritis', which occurs occasionally, which must be distinguished from transient albuminuria; hepatic impairment and rare life-threatening hematologic disorders such as thrombocytopenia purpura, hypoplastic and aplastic anemia, granulocytopenia, and "secondary" anemia. Eosinophilia often precedes dermatitis and is an indication of allergic reaction to chrysotherapy. Some of these side effects appear to be due to hypersensitivity reactions (Brass and Lapp, 1969; Wiontzek and Schmidt, 1970; Schoepf et al., 1970) which occur because gold therapy is immunostimulatory, (Altmann and Eberl, 1969) rather than immunosuppressive as is corticosteroid therapy (Persellin et al., 1967). Thus, when allergic or hypersensitivity reactions occur, treatment with corticosteroids or other immunosuppressants is possible. In addition to corticosteroid therapy for the hyperimmune reactions, many rheumatologists believe that many toxic reactions can be minimized and even eliminated by proper control of the patient's dosage schedule and his regimen for basic management. Severel Belgian workers have shown that the concurrent administration of calcium salts with gold therapy reduces the incidence of toxic effects (Vanslype et al., 1970). Furthermore, when toxic reactions do occur there is available specific treatment in the form of immunosuppressants, as indicated above, and of penicillamine and BAL (dimercaprol), which are chelating agents for heavy metals (Forestier, 1968; Eyring and Engelman, 1963; Blubin et al., 1962; Wiontzek and Schmidt, 1962; Strauss et al., 1952). Goodman and Gilman (1965) suggested that gold compounds are contraindications in the presence of renal disease, infectious hepatitis or blood dyscrasias of any sort, in urticaria, in eczema, in colitis, and during the conduct of radiation therapy. Freyberg et al. (1941) have further recommended that gold therapy be avoided during pregnancy as well as in patients with other drug idiosyncrasies or congestive heart failure. Although there is no evidence for marked differences in the toxicity of soluble gold compounds in man, it has been found that gold thioglucose specifically induces hyperphagia and obesity in mice and in rats (Baile et al., 1970). The hyperphagia is due to degeneration of the axons leading from the ventromedial hypothalamus to the lateral area of the hypothalamus, thus i.e. to damaging the 'satiety center' of the animal. Simultaneous administration of glucose with aurothioglucose exacerbates the lesion, while the presence of diabetes or the administration of a glucose antagonist such as 2deoxy-D-glucose diminishes this cerebral effect of the drug. The mechanism of action of gold thioglucose in producing obesity in mice and rats has now been established as one of necrosis of the ventromedial hypothalamus, which is specific for this gold compound. Bipiperidyl mustard has also been shown to penetrate the satiety center and to cause a similar necrosis of this area. As a result, obesity is produced by both agents, but not by other gold compounds which do not reach this center; the deposition of gold is a secondary event and not causative of obesity (Rutman et al., 1966).

3. BIOLOGICAL AND BIOCHEMICAL ACTION OF GOLD COMPOUNDS Although the clinical usefulness of gold compounds in rheumatic and inflammatory diseases has been unequivocally established, there is no acceptable mechanism to explain the therapeutic action of chrysotherapy. Gold compounds are not immunosuppressive, in contrast to other drugs used for arthritis, especially the corticosteroids (Persellin et al., 1967). In fact, the finding of Altman and Eberl (1969) that /3- and 7-globulins in serum of patients receiving chrysotherapy are elevated by as much as 50 per cent suggests that gold compounds may even stimulate immune reactions. This immunostimulation cannot be the mechanism of the therapeutic activity of the gold compounds, but may serve as a basis for some of the undesirable side effects. Similarly,

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even though gold compounds were first used therapeutically because of their supposed antibacterial activity, the fact that they are active against arthritis in animals caused by such diverse agents as streptobacillus moniliforms, pleuropneumonia-like organisms, formaldehyde,/3-hemolytic streptococcus, and exudate from the Murphy lymphosarcoma suggests that their action is on a condition and not on a specific bacterial agent (Goodman and Gilman, 1965). Gold salts have been shown to release lysosomal hydrolases from macrophages and other cells (Persellin et al., 1963; Ennis et al., 1968) which are considered to be involved in the disease process of chronic rheumatoid arthritis. Bollet and Shuster (1960) showed that gold sodium thiomalate, when given subcutaneously to rats, inhibits transaminase and the formation of glucosamine-6-phosphate in connective tissue but not in liver. These observations may well be clues to the mechanism of action of gold salts in the treatment of arthritis. The absorption of gold compounds and their distribution in tissue depend on their aqueous solubility and the route of administration. Gold sodium thiosulfate and gold sodium thiomalate, for example, which are water soluble, are rapidly absorbed following parenteral administration; however, water insoluble preparations given as oil suspensions are poorly absorbed (Freyberg et al., 1951; Block et al., 1941, 1942, 1944). Gold compounds are poorly absorbed from the gastrointestinal tract (Kleinsorge et al., 1959), with the exception of the recently introduced experimental drug, triethylphosphinogold chloride (SKF 36914) (Walz et al., 1971), which appears to be well absorbed when given orally. The distribution of gold has been studied in man and animals (Freyberg et al., 1941; Block et al., 1941) and it has been found that gold is bound primarily to plasma proteins. Eberl and Altman (1969) followed serum gold after the administration of gold sodium thiosulfate (water-soluble) i.v. levels and gold keratinate (water-insoluble) i.m. to patients with inflammatory and rheumatic diseases. Their data show that the soluble gold thiosulfate reached a peak of about 20/xg of gold per ml within minutes, remained at this high level for an hour, and then declined slowly, so that the level had dropped 75 per cent within 4 days. On the other hand, the level of serum gold reached a maximum of 3/xg of gold per ml of serum within 6hr of the administration of the insoluble keratinate, and declined after the twenty-fourth hour to a low of about 16 per cent of the peak level on the fourth day after the treatment. Although gold salts circulate as gold-protein complexes, the nature of these is not known. Excretion is primarily via the kidney, but some gold finds its way into the feces. The rate of excretion in the urine does not directly reflect the concentration in the plasma, although it diminishes as the concentration in the plasma drops in any individual subject (Krusius et al., 1970). There is retention of gold during therapy, but very little is known about the metabolic fate of this element or its mechanism of action. It is known, however, that when the compound is the water soluble form, accumulation is greatest in the kidney, less in the liver, and least of all in the spleen (Goodman and Gilman, 1965; Freyberg, 1966). When the gold compound is of the water-insoluble type there is greater accumulation in the liver and spleen than in the kidney. The retention of gold by tissues is of such tenacity that the metal can be detected in the urine of patients to whom it has not been given for 1 year (Goodman and Gilman, 1965). These observations may well be the basis for understanding the variability of clinical responses and toxic side effects. Krusius et al. (1970) have reported recently that high plasma levels were correlated with good clinical response and low ones with poor response, and the highest plasma levels were found in those with toxic reactions. Urinary levels in general corresponded with plasma levels. In a recent paper, Stuve and Galle (1969) showed that gold concentrates in the kidney, primarily in the mitochondria of the proximal tubules, and the number of mitochondria affected are proportional to the dose. The accumulation of gold destroys the mitochondria, and they are expelled into the tubular lumen. After withdrawal of the drug, the tubular structure returns to normal. All of the gold drugs are Au ~÷ compounds, which are not readily reduced to metallic gold; hence patients do not exhibit widespread deposition of the metal in skin or mucous membranes, similar to that seen in argyria.

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