Search

Gold based drugs and their metabolites have been characterized using reversed phase, ion pairing chromatography with an inductively coupled plasma mass spectrometer as an element specific detector. For a patient receiving gold sodium thiomalate the principal gold species in the urine is [Au(CN)2]-, which is also seen in a low molecular weight infiltrate of the blood. The same compound is also identified in the urine and blood of a patient taking auranofin and in patients taking solganol. This represents the first identification of a specific gold metabolite in biological fluids taken from patients undergoing gold therapy and the first evidence that different gold drugs have common metabolites.

Auranofin (AF) differs significantly from gold sodium thiomalate (GST) in formulation, i.e., aurous gold is stabilized by dual sulfur and phosphorus ligands, has hydrophobic rather than hydrophilic characteristics, and lacks ionic charge. These attributes facilitate: oral absorption of AF, plasma membrane penetration, increase in intracellular lymphocyte gold concentration and perhaps thereby influence lymphocyte function. AF therapy was observed to affect primarily T rather than B lymphocyte function in 16 RA subjects receiving 6 mg of AF per day for an average of 45 weeks (range 20-74 weeks) compared with GST-treated RA subjects. Lymphocytes from AF-treated subjects manifested prompt and sharp declines in mitogen-induced lymphoproliferative response (LPR); suppressed response to skin testing with dinitrochlorobenzene (DNCB); and blebbing of lymphocyte membranes as shown by scanning electron microscopy. Suppression of LPR with AF was approximately 60% after the first week and 80% after 20 weeks of therapy, contrasting with 0% and 30% for the respective intervals in GST-treated subjects. DNCB skin testing of AF patients, indicated 11 of 14, failed to respond, whereas all GST patients responded. Local or systemic fungal, bacterial and/or opportunistic infections were not encountered. The effect of AF on B cell effector function, e.g., suppression of immunoglobulins and rheumatoid factor titer, was less marked when contrasted with GST therapy in RA subjects, as previously reported.

The binding of gold to peripheral erythrocytes and serum protein fractions was studied during chrysotherapy of 1 to 2 years' duration in 43 patients with rheumatoid arthritis. In 45% of the patients more than 10% of the gold was found to be strongly bound to blood cells. 5--15% of the metal is bound to non-albumin protein fractions at serum gold concentrations larger than 2 microgram/ml. In contrast to the cellular binding of gold the relative binding of gold to non-albumin proteins was inversely proportional to the serum concentrations. Binding to neither blood cells nor to non-albumin protein fractions was found to be correlated with clinical parameters.

Pharmacologic management of juvenile rheumatoid arthritis is only one of several modalities necessary for effective control. The stepping stones to proper management include a planned long-range program, physical therapy with swimming, good health habits, and consultation with other health professionals who are part of the management team. Pharmacologic therapy includes nonsteroidal anti-inflammatory drugs initially, occasionally corticosteroids, and slow-acting antirheumatic drugs, including injectable gold when therapeutic response is inadequate. Early experiences with oral gold are reported here. Auranofin (triethylphosphine gold) was administered to 21 patients with juvenile rheumatoid arthritis during a segment I, open ended, open-label, noncontrolled trial designed to establish safety and preliminary efficacy. Initial dosage was 0.1 mg/kg per day; incremental increases to 0.2 mg/kg per day were allowed (with usual increase to 0.15 mg/kg per day). Aspirin (80 mg/kg per day) or tolmetin (20 to 40 mg/kg per day), or naproxen (400 to 600 mg/m2 per day) were allowed as rapidly acting antiinflammatory agents. Stable measurable plasma concentrations of gold were attained in all patients during the study. More than half the patients sustained clinically significant improvement (greater than 25 percent) with regard to the number and severity of joints with swelling, pain on motion, and tenderness. In nine of the 19 patients, the total number of joints with active arthritis decreased by at least 25 percent. All articular disease indices measured indicated improvement of group mean changes between the initial and final visit. Eleven of 16 patients with an elevated erythrocyte sedimentation rate showed decreases of at least 25 percent. The group given higher dosages had a greater proportion of responders in regard to decreases in erythrocyte sedimentation rate (nine of 11 patients). Four of six patients whose serums contained rheumatoid factor showed decreases in the titers. Discontinuation of auranofin was necessary in two patients: one because of headache and one because of hematuria and anemia associated with a severe flare-up of polyarticular disease. The results from this trial reveal sufficient patient improvement to plan a double-blind trial of auranofin in children with juvenile rheumatoid arthritis.

Cyanide markedly increased the rate of uptake of gold by red blood cells when incubated with sodium aurothiomalate, a polymeric gold complex. Thiocyanate had no significant effect on gold uptake. The effect of cyanide was demonstrated to be due to the conversion of aurothiomalate to the complexion, aurocyanide, which is rapidly taken up by red blood cells. At a low ratio (1:20) of cyanide to aurothiomalate, cyanide appeared to act as a shuttle to carry gold into red blood cells. Tobacco smoking is known to increase the concentrations of gold in red blood cells in patients treated with aurothiomalate. The present data indicate that this effect of smoking is most likely due to cyanide inhaled in tobacco smoke and not to thiocyanate, a circulating metabolite of cyanide. An effect of cyanide on the uptake of polymeric gold complexes to target cells such as polymorphonuclear leukocytes and monocytes is suggested.

As used clinically, Myocrisin appears to contain largely polymeric (Autm)n, in which thiomalate (tm) sulphurs bridge between Au(I) ions, together with small amounts of a more reactive gold-bound thiomalate, and free thiomalate, as well as glycerol, unidentified yellow-products from autoclaving and phenylmercury adducts. Solganal usually contains thioglucose sulphinic acid as an impurity. Auranofin, on the other hand, has been crystallised. It is monomeric and Au(I) is almost linearly coordinated by P and S from triethylphosphine and tetraacetyl-beta-D-thioglucose, the latter adopting the chair conformation in the solid state and in solution. The major reaction of auranofin in acidic aqueous solutions appears to be hydrolysis of the sugar acetyl groups but other products arise if methanol is also present in the medium. NMR methods are used to examine in vitro the partition of auranofin between plasma and blood cells. The displacement of the thioglucose ligand and release of PEt3 from gold as OPEt3 are discussed.

We studied the dose-response to a new oral gold compound in 28 patients with definite rheumatoid arthritis, divided in 4 groups of 7 patients, each treated with different doses of auranofin for 3 months. Clinical and laboratory parameters were recorded weekly, and blood gold levels (BGL) measured by atomic absorption spectroscopy. Six and 9 mg daily doses of auranofin were most effective based on clinical and laboratory results. Correlation studies between BGL and percent decrease of humoral measurements, within the 3 months were statistically were statistically significant. Mean BGL, associated with clinical improvement, reached 0.73 microgram/ml, and was accompanied by a 17.6% decrease from initial value of IgG, 17.1% of alpha 2-globulin, 48.9% of RF titer and 25.9% of ESR.

During 20 weeks of aurothioglucose therapy, gold in a mother's serum and breast milk and her nursing infant's serum and urine were measured. The mother's steady state plasma gold was 4.05 mg/l; it was 0.041 mg/l in breast milk. Only 0.0255 mg gold appeared in the breast milk/24 h. We calculated that only 0.1785 mg gold (0.71% of the weekly dose) would appear in the breast milk over a week. No gold (less than 5 X 10(-7) mg/l) was found in the infant's plasma or urine. It is very unlikely that more than minute amounts of gold are absorbed from the mother's breast milk when breast feeding an infant.

The intramuscular (gold sodium thiomalate and aurothioglucose) and the orally (auranofin) administered gold compounds exhibit contrasting patterns of absorption, excretion and body tissue and fluid levels. The parenteral compounds are fully absorbed after injection but negligibly absorbed orally. Approximately 25% of the gold in auranofin is orally absorbed. Serum gold levels peak several hours after injection during conventional weekly treatment, attaining concentrations of 600-800 micrograms/dl, and then decline gradually, reaching 300-350 micrograms/dl before the next injection. Whole blood gold levels with auranofin vary from 10 to 90 micrograms/dl with doses of 1-9 mg/day. Blood gold levels plateau after 6-8 weeks with the injectable compounds and after 12 weeks with oral gold, reflecting the shorter blood half-life of gold sodium thiomalate (5.5 days) than of auranofin (17-26 days). A larger fraction of gold is within or attached to circulating blood cells, especially erythrocytes, with auranofin than with injectable gold. Fourty percent of the administered dose is excreted during injectable chrysotherapy, and 75-100% is recovered in excreta with auranofin. Parenteral gold is excreted primarily in urine (70%) while auranofin gold is recovered primarily in faeces (95%). Approximately 43% of intravenous radiolabelled gold sodium thiomalate is retained in the body at 60 days and 30% at 180 days; only 15% of radiolabelled auranofin remains at 10 days and less than 1% at 180 days. During injectable therapy, the total body burden of gold rises steadily; preliminary studies suggest minimal tissue accumulation with auranofin.

Auranofin is a chemically unique gold coordination complex with demonstrated antiarthritic properties on oral administration. Its pharmacokinetic and immunologic profiles are distinct from injectable gold compounds. When auranofin is added to a regimen of salicylates and/or a nonsteroidal antiinflammatory drug for the treatment of RA, significant additional therapeutic benefit is observed. Published studies indicate that auranofin given 6 mg per day approaches the efficacy of parenteral gold salts in the treatment of rheumatoid disease. Noticeable improvement in clinical and laboratory parameters of disease activity has been observed by the third month of auranofin therapy. Further benefit occurs in some patients during the remainder of the first year of treatment. In the more than 3,000 patients treated with auranofin, the most frequently reported side effects were gastrointestinal (mainly diarrhea) and mucocutaneous. Most side effects were mild in nature and the withdrawal rate due to all adverse reactions averaged 11%. Auranofin differs from injectable gold by producing more gastrointestinal but fewer mucocutaneous reactions. The severity of these reactions is less with auranofin and causes fewer withdrawals from therapy.

Evidence on the action mechanisms of gold salts in the treatment of rheumatoid arthritis is still inconclusive. The intracellular localization of the place of action is likely. Therefore not only the serum gold levels but also the intracellular concentration of gold are of special interest. We measured the gold concentration in the serum and in the blood cells after in vitro application of aurothiomalate (Tauredon), gold keratinate (Auro-Detoxin) and triethylphosphine-gold (Ridaura) and in blood samples of patients undergoing these gold salts treatments. Cell-bound concentrations were found to vary extensively as a function of the gold compound used. While no or very little gold was present intracellularly after administration of the 2 parenteral drugs, up to 40% of the circulating gold was found to bind to the cells after administration of the triethylphosphine compound for gastro-intestinal absorption. The red cell concentration was more or less the same as that in the extracellular compartment. Gold apparently accumulated in the white cells, because the cell-bound concentration relative to unit volume was up to 20 times higher than the plasma level. The method used did not offer any information on the actual binding site of gold in white cells, i.e. cytoplasm versus nucleus versus cell membrane.

The new oral gold compound auranofin differs pharmacokinetically from the existing injectable gold compounds such as gold sodium thiomalate. Following a standard 50 mg intramuscular injection of gold sodium thiomalate, plasma gold levels rise sharply, peak between 400 and 800 micrograms/dl in approximately two hours, then decline to approximately 300 micrograms/dl by seven days. With repeated 50 mg weekly injections, stable plasma concentrations are gradually achieved, although absolute levels vary greatly among individual subjects. On the other hand, auranofin is associated with lower (50 to 70 micrograms/dl) and more predictable plasma concentrations. Single-dose kinetic studies using isotopically labelled gold show that the plasma disappearance half-time for gold sodium thiomalate is relatively rapid (approximately six days) compared with 17 days for auranofin. Both compounds are retained within the body over prolonged periods. Retention of auranofin is much less, about 1 percent of the original tracer dose remaining at 180 days, compared with more than 30 percent retention of gold sodium thiomalate. Excretory pathways are notable different. The majority of gold sodium thiomalate (greater than 70 percent) is excreted by the kidneys, with the remaining fraction appearing erratically in the stool. In contrast, the enteric pathway represents the major excretory route for auranofin, with nearly 85 percent of the dose eventually recoverable in the stool and less than 15 percent in the urine. In human subjects, parenterally administered gold is almost universally dispersed among body tissues, although highest concentrations occur in the organs of the reticuloendothelial system and the adrenal and renal cortices. Comparable studies are not available for auranofin, but animal studies show comparatively less affinity for liver, kidney, and spleen. To date, attempts to correlate the pharmacokinetics of the injectable gold compounds with clinical response and toxicity have been largely unsuccessful. The distinctive pharmacokinetic profile of auranofin, when compared with gold sodium thiomalate, may nonetheless account in part for the clinical and pharmacologic differences between these compounds.

Carbon rod atomic absorption analysis (CRA) was applied to the quantiation of gold lymphocyte content (GLC) during chrysotherapy. Sensitivity and accuracy of CRA compared favorably with 195Au isotopic scintillation counting, circumventing the limitations and hazards of the latter in clinical applications. Picogram gold quantification of limited sample volume, less than 10 ml blood, e.g., 10(4)-10(5) lymphocytes (5 microliters) containing 5-10 pg was achieved. GLC after IM administration increased significantly in 60% of patients; for the remainder, GLC was observed to be independent of plasma gold content or cumulative dosage. GLC during auranofin administration (6 mg/day p.o.) approached values for IM gold despite significantly lower plasma levels. Unique sensitivity of CRA enables analysis of GLC under therapeutic conditions that could elucidate whether gold alters functional determinants.

Unbound serum gold (UBSG) has received little attention, possibly because of rapid in vivo decay and in vivo concentration below the range of existing analytical procedures. We have recently developed a methodology enabling quantitation and study of UBSG during chrysotherapy to assess effects on cellular functions. UBSG after gold administration is labile, declining rapidly after attaining peak values at which lymphocyte mitogen response and polymorphonuclear phagocytosis were observed to be suppressed. Oral gold, i.e., auranofin, 3 mg BID as compared to systemic chrysotherapy 50 mg/wk, resulted in a higher percentage of UBSG to total serum gold.

Three different methods of determining the cell-bound gold concentration were compared in patients given intramuscular and oral chrysotherapy for rheumatoid arthritis. We found a strong correlation between the different methods and no difference between 2 washing procedures.

The pharmacokinetics of gold sodium thiomalate (GST) and triethylphosphine gold (auranofin; AF) are different. Gold sodium thiomalate (GST) is completely bioavailable while only 15-25% of auranofin (AF) is absorbed. Protein binding of AF occurs to a larger extent to macroglobulins than does GST and total body retention of GST is much greater than AF at six months (30% versus approximately 1%). While terminal serum half-lives are approximately equal, total body half-lives are 250 days for GST and 69 days for AF. In addition, excretory pathways contrast markedly, with 85% of AF appearing in the feces while only 30% of GST is excreted by this route; 15% of AF gold appears in the urine and approximately 70% of GST gold is excreted via this route. With all the above differences one would expect that organ and cellular distribution of these compounds would differ. While gold from both drugs is concentrated in kidney, the percent of the dose found in the kidneys is less for AF than GST, at least in animals (0.4% vs 4.8%). Minute quantities are found in other organs but more study is needed to more clearly define organ distribution of these gold compounds, particularly in man.

Three children with juvenile rheumatoid arthritis were given a single oral dose of approximately 0.1 mg/kg of auranofin. Blood concentrations up to 49 ng/ml were detectable at 24 h (earliest sample) and remained detectable for at least 2 weeks (final sample). Disappearance of measurable gold from both the blood and serum appeared to be linear through time. None of the patients experienced significant laboratory abnormalities nor adverse reactions. Gold levels attained in these children were somewhat lower than those seen in adults administered an equivalent dose.