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PubMed1986

Gold sodium thiomalate activates latent human leukocyte collagenase.

Gold sodium thiomalate, a drug used widely in the therapy of rheumatoid arthritis, was found to be an activator of latent human polymorphonuclear leukocyte collagenase. The activation was demonstrated by two distinct and independent collagenase assays: by recording with a spectrophotometer at 227 nm the enzyme-induced increase in ultraviolet difference absorbance of native type I collagen connected to the cleavage of collagen at 37 degrees C [(1986) Eur. J. Biochem. 156, 1-4] and by SDS-polyacrylamide gel electrophoresis analysis of formation of specific products of collagen resulting from collagenase cleavage at 25 degrees C. Activation of latent collagenase by gold sodium thiomalate appeared to be of the same magnitude as by the known activator phenylmercuric chloride.

Electrophoresis, Polyacrylamide Gel↗

PubMed1987

A reaction between captopril (a high blood pressure drug) and gold(I)-thiomalate.

A reaction of gold(I) thiomalates [Au(tm)], "Myocrisin" (an antiarthritic drug), with captopril (a high blood pressure drug) was carried out in aqueous solution at pH 7.20 using 13C NMR spectroscopy. Captopril, which exists in the cis (c) and trans (t) isomer forms, binds strongly with gold(I), ejecting thiomalate (Htm) as free ligand into solution.

Captopril↗

PubMed1992

The 13C NMR study of the binding of gold(I) thiomalate with ergothionine in aqueous solution.

The interaction of gold(I) thiomalate (Autm) (Myocrysine) with ergothionine (ErSH) has been studied in aqueous solution at pH 7.4. It was found that ErSH forms a ternary complex of the type ErS-Au-tm at a 1:1 mole ratio; unlike other thiols (e.g., cysteine and glutathione) it does not eject thiomalate (Htm) as a free ligand. However, in the presence of glutathione (GtSH), both ligands, ErSH as well as Htm, from the ErS-Au-tm complex were freed. The 13C NMR chemical shifts of C-2 resonance of ergothionine in the presence of Autm shifts greater than imidazolidine-2-thione (Imt) and 1,3-Diazinane-2-thione (Diaz), indicating the stronger complexation of ErS-Au-tm compared to Imt-Au-tm and Diaz-Au-tm.

Carbon Isotopes↗

PubMed1984

Antithrombin activity of gold sodium thiomalate.

Gold sodium thiomalate has been shown to inhibit serine esterase enzymes isolated from the lysosomes of white cells. We demonstrate for the first time to our knowledge that gold sodium thiomalate is inhibitory to the serine esterase thrombin in its interaction with washed human platelets, human platelet-rich plasma, and human platelet-poor plasma. Since thrombin is a serine esterase phylogenetically related to the serine esterases elastase and cathepsin G, the most likely mechanism of action is an interaction of the gold thiol complex with one or all of the four cysteine-cysteine disulfide bridges of the thrombin molecule.

Gold Sodium Thiomalate↗

PubMed1983

Inhibition of lymphocyte activation by gold sodium thiomalate.

Activation of lymphoid cells by both T and B cell mitogens was inhibited by gold sodium thiomalate (GST). The action of GST did not appear to be exerted at early stages of lymphocyte activation. Inhibition by GST was sustained throughout 4 days of culture. The inhibitory effect of GST was reduced at low serum concentrations. Sodium thiomalate and sodium chloroaurate were also able to inhibit lymphocyte activation.

Animals↗

PubMed2004

Gold sodium thiomalate improves membrane potential impaired by high-frequency stimulation.

Effects of gold sodium thiomalate (GSTM) on membrane potential and tetanus tension were examined to elucidate whether the gold compound improves mechanical and electrical muscle dysfunction produced by continuous repeated stimulation of frog skeletal muscles. Continuous stimulation (50 Hz for 2 min, 0.05 ms pulse duration) to the sartorius muscle depolarized the membrane, decreased action potential amplitude, and prolonged action potential duration. GSTM (0.1 mM), unlike thiomalic acid (0.1 mM), markedly decreased impairment of these electrical parameters produced during the stimulation period. In the presence of 500 units/mL of catalase, fatigue stimulation still lengthened by 1.5-fold the half-duration of the action potential after a 5-min rest. The prolongation was, however, smaller than that in controls (no catalase). Application of both catalase and GSTM led to no further changes in action potential compared with the application of catalase alone. GSTM did not affect resting tension of single toe muscle fibers though it suppressed the maximum tension after continuous stimulation. These findings suggest that GSTM can inhibit excitable dysfunction of skeletal muscles subjected to continuous stimulation and that such protective effects of GSTM may be partially mediated by H2O2.

Animals↗

PubMed1979

Alterations in human monocyte structure and function induced by incubation with gold sodium thiomalate.

The effect of in vitro indubation with gold sodium thiomalate (GST) on the morphology and functional activity of human mononuclear phagocytes (Mphi) was examined. Human peripheral blood Mphi that had been incubated with GST (25 micrograms/ml) for 4 days developed large intracytoplasmic vacuoles. Similar vacuolization developed after incubation with gold chloride but not with thiomalic acid. GST pre-incubation also induced a number of functional alterations in Mphi. GST incubation had little effect on glass adherence or FC receptor-mediated particle binding but markedly diminished pinocytosis of horseradish peroxidase and phagocytosis of IgG opsonized erythrocytes. These data indicate that the action of GST in rheumatoid arthritis may result from its capacity to alter the functional capability of Mphi.

Cell Survival↗

PubMedDate not supplied

Effect of gold thiomalate on cell proliferation and collagen synthesis of synovial cells in culture.

Human synovial cells from cases of rheumatoid and osteoarthritis were cultured and at their 3-5 passages, were treated with gold thiomalate. At early-log phase gold thiomalate arrested the proliferation of cells. However, at confluent state shere was a slight proliferation of synovial cells. This was followed by an increase in prolyl hydroxylase, collagen and protein synthesis, indicating that gold salts directly stimulate the synovial cells.

Arthritis, Rheumatoid↗

PubMed1994

Gold sodium thiomalate down-regulates intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression on vascular endothelial cells.

We examined whether antirheumatic drugs alter cytokine- or lipopolysaccharide-induced expression of adhesion molecules on vascular endothelial cells. Human umbilical cord vein endothelial cells were co-cultured with various antirheumatic drugs in the presence of inflammatory cytokines, and adhesion molecule expression was measured by cell enzyme-linked immunosorbent assay and Northern blot analysis. Among these antirheumatic drugs, gold sodium thiomalate significantly inhibited intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression on vascular endothelial cells and suppressed cellular binding between human monocytic cell lines, including U937 and HL-60 cells, and interleukin-1 beta-stimulated vascular endothelial cells. It is speculated that down-regulation of adhesion molecules might be one of the novel mechanisms of action of gold sodium thiomalate.

Adrenal Cortex Hormones↗

PubMed1985

Ankylosing spondylitis and rheumatoid arthritis in a patient with Paget's disease. Differential effects of indomethacin, D-penicillamine, or gold sodium thiomalate in the respective arthritides.

A patient developed both ankylosing spondylitis and rheumatoid arthritis, each of which responded to D-penicillamine or gold sodium thiomalate and indomethacin, respectively. The patient was both HLA-B27 and -DR4 positive. In addition, he was found to have Paget's disease of bone, which has required no treatment.

Aged↗

PubMed1996

Species differences in the renal toxicity of the antiarthritic drug, gold sodium thiomalate.

Two gold compounds, gold sodium thiomalate (AuTM) and auranofin, are presently in clinical use in therapy of rheumatoid arthritis. In these studies, AuTM administered to Sprague-Dawley rats and three strains of mice, Swiss-Webster, C3H/HeJ, and DBA/2J, were studied with regard to its effect on liver and renal monooxygenases, metallothionein contents, and serum levels of alanine aminotransferase and urea nitrogen. These effects of AuTM were compared to those of cadmium, since the latter metal has exhibited tissue and species differences in the induction of metallothionein. Benzo(a)pyrene hydroxylase and benzphetamine N-demethylase activities were not altered by AuTM in livers of rats and the three strains of mice. Benzo(a)pyrene hydroxylase activity was significantly decreased in rat kidney, whereas this enzyme activity was not affected in the kidneys of mice. In rats, AuTM caused a sevenfold induction in liver metallothionein, while in mice, liver metallothionein was induced twofold in Swiss-Webster mice and about fivefold in the inbred strains. AuTM caused minimal changes in renal metallothionein contents in the three strains of mice studied. Serum alanine amino-transferase, an indicator of hepatotoxicity, was not altered by AuTM in rats and mice studied. Blood urea nitrogen, an indicator of kidney dysfunction, was increased threefold in rats, but not in AuTM-treated mice. These data demonstrate that AuTM, a nephrotoxic agent in rats and humans, showed no nephrotoxic effects in the mouse strains studied here.

Alanine Transaminase↗

PubMed1977

Acute myocardial infarction following gold sodium thiomalate induced vasomotor (nitritoid) reaction.

A vasomotor (nitritoid) reaction occurred following an initial injection of gold sodium thiomalate (GST; Myochrysine) in a 69-year-old man with rheumatoid arthritis (RA). An acute anterior wall myocardial infarction, documented by serial electrocardiographic and serum enzyme changes, developed immediately thereafter. A second patient, a 49-year-old man with RA and a history of GST-associated vasomotor reactions, was monitored clinically and electrocardiographically after GST administration. Sinus tachycardia developed and peripheral blood pressure fell within 2 minutes of injection, simultaneous with the onset of vasomotor symptoms. Vasomotor reactions from GST may compromise myocardial perfusion by their action on arteriolar smooth muscle, and thus result in peripheral vasodilatation, or they may act by adrenergic discharge initiated by such a reaction, and thus increase myocardial work and oxygen demand. Aurothioglucose (Solganal), rarely produces vasomotor reactions, and may be preferred to GST in elderly RA patients with concomitant cardiovascular disease or atherosclerosis.

Aged↗

PubMed1983

Comparison of auranofin, gold sodium thiomalate, and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial.

A prospective controlled, double-blind multicenter trial compared placebo, auranofin (an orally administered gold complex), and parenteral gold sodium thiomalate (GST) in patients with active rheumatoid arthritis (RA). Of 193 patients who received any treatment, the only important improvement identified for either auranofin or GST was for pain/tenderness scores. When 161 patients who completed 20 weeks of treatment were examined, both auranofin and GST treatments were superior to placebo as measured by improvement in number of painful and/or tender joints, joint pain/tenderness scores, physician's assessment of disease activity, and decrease in erythrocyte sedimentation rate when elevated at entry. GST was superior to placebo in improvement of joint swelling scores, anemia, thrombocytosis, and rheumatoid factor. No drug-related remissions were observed. The only statistically significant advantages of GST over auranofin for efficacy were an increase in hemoglobin concentration and decrease of thrombocytosis with GST. Withdrawals for adverse effects were 5 times more frequent with GST treatment. Thrombocytopenia, proteinuria, elevated liver enzymes, "nitritoid" reactions, and "gold pneumonitis" were observed only in the GST treatment group. These results confirm that both parenteral and oral gold may be effective for the treatment of RA, that GST tends to show greater efficacy than auranofin, and that auranofin has fewer significant adverse effects than GST. However, long-term benefits, tolerability, and safety cannot be inferred from this study.

Adolescent↗

PubMed1985

Lack of correlation between blood gold concentrations and clinical response in patients with definite or classic rheumatoid arthritis receiving auranofin or gold sodium thiomalate.

We investigated the correlation between whole blood gold concentrations and clinical outcomes in 59 auranofin-treated patients and 51 gold sodium thiomalate-treated patients who completed a 21-week, placebo-controlled, multicenter parallel trial. Whole blood gold concentrations did not correlate with clinical outcome, as assessed by changes in joint tenderness, joint swelling, or Westergren erythrocyte sedimentation rate. They also did not correlate with toxic reactions necessitating withdrawal from the study.

Adolescent↗

PubMed1987

Effects of gold sodium thiomalate on interferon stimulation of C2 synthesis and HLA-DR expression by human monocytes.

Gamma-interferon (gamma-IFN) is a T cell-derived lymphokine that has potent macrophage-activating properties. It increases Fc receptor density, increases the formation and release of reactive oxygen intermediates, increases the synthesis and release of complement cascade proteins, especially C2 and factor B, and increases class II (HLA-DR) antigen expression. These effects may play a role in the potentiation of inflammation in rheumatoid arthritis. We examined the possibility that gold sodium thiomalate (GST), an effective treatment for rheumatoid arthritis, would inhibit gamma-IFN-mediated stimulation of monocyte/macrophages. GST in concentrations attainable in vivo was shown to inhibit both spontaneous and gamma-IFN-stimulated C2 production up to 50%. GST inhibition could be only partially overcome with increasing concentrations of gamma-IFN. In addition, GST inhibited gamma-IFN-stimulated HLA-DR expression at the highest concentrations tested (20-50 micrograms/ml). GST alone in low concentrations (0.1-5 micrograms/ml) was found to increase HLA-DR antigen expression as quantitated by several methods, including flow cytometry, cell surface enzyme-linked immunosorbent assay, and Western blotting. This GST-stimulated increase in HLA-DR antigen expression paralleled an increased ability of monocytes to present antigen. The mechanism by which low concentrations of GST stimulate HLA-DR antigen expression is unclear, but was shown by 35S-methionine cell labeling not to involve increased HLA-DR protein synthesis.

Cell Separation↗

PubMed1988

Inhibition of in vitro proliferative response of cultured T lymphocytes to interleukin-2 by gold sodium thiomalate.

Gold sodium thiomalate (GST), in concentrations attainable during chrysotherapy for rheumatoid arthritis, significantly inhibited the proliferative responses of cultured T cells stimulated by interleukin-2 (IL-2). The observed suppression was not related to altered kinetics, cell death, or interference with the binding of IL-2 to cell surface receptors. It appeared that GST affected an early step in the proliferative process, since maximum inhibition was obtained by the addition of GST within 4 hours of stimulation; progressive reduction of suppression was observed when GST was added later. Significant inhibition occurred when cultured T cells were preincubated for 24 hours with GST and washed prior to IL-2 stimulation, although the degree of suppression was decreased. Thus, inhibitory activity was not dependent on the continued presence of GST throughout culture. These findings suggest that there is a direct inhibition of T lymphocytes by GST, which may be important in immunomodulation by gold compounds.

Binding Sites↗

PubMed1988

A controlled trial comparing sulfasalazine, gold sodium thiomalate, and placebo in rheumatoid arthritis.

One hundred eight-six patients with active rheumatoid arthritis were evaluated in a double-blind, randomized study that compared treatment with sulfasalazine (SSZ) (2 mg/day), gold sodium thiomalate (GST) (50 mg/week), and placebo (PBO). The 37-week course of therapy was completed by 109 patients. While marked improvement was seen in all 3 treatment groups, the only statistically significant differences between SSZ or GST and PBO were in a decreased erythrocyte sedimentation rate and increased grip strength in the right hand. GST is known to be superior to PBO, and the response of the GST-treated group was similar to that seen in other trials. The response of the PBO group, however, was much greater than in other placebo groups we have studied. SSZ was similar in efficacy to injectable gold, but was better tolerated. Because of adverse drug reactions (most commonly, rash, stomatitis, and proteinuria), 41% of patients were withdrawn from the GST treatment. Untoward drug effects (most frequently, rash and gastrointestinal distress) caused 16% of patients to be withdrawn from SSZ therapy.

Adolescent↗

PubMed1990

Effects of gold sodium thiomalate and tenidap sodium (CP-66,248-2) on a model of macrophage differentiation using HL-60 cells.

We studied the effects of gold sodium thiomalate (GST) and a new antirheumatic drug, tenidap sodium ([Z]-5-chloro-2,3-dihydro-3-[hydroxy-2-thienylmethylene]-2-oxo-1H- indole-1-carboxamide, sodium salt), previously known as CP-66,248-2, in a model system of macrophage differentiation using a myelomonocytic cell line. HL-60 cells can be stimulated by vitamin D3 to differentiate along a monocytic pathway. Monocytic HL-60 cells express CD14 (Leu-M3), a macrophage surface marker, and develop the capacity to produce the second complement component (C2) in response to stimulation with cytokines such as gamma-interferon. The effects of GST and tenidap sodium were compared with the effects of dexamethasone and a variety of nonsteroidal antiinflammatory drugs in this model system. We found that GST inhibited the capacity of HL-60 cells to produce C2 but did not inhibit the expression of CD14. Tenidap sodium inhibited C2 production as well as CD14 expression, and it partially reversed the decrease in 3H-thymidine incorporation by HL-60 cells, which accompanies monocytic differentiation. At concentrations that inhibited C2 production by HL-60 cells, tenidap sodium did not inhibit C2 production by monocytes. Neither dexamethasone nor the other nonsteroidal antiinflammatory drugs tested possessed these activities. Thus, both GST and tenidap inhibit markers of monocytic differentiation in HL-60 cells, and this activity may relate to their antirheumatic activities.

Cell Differentiation↗