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PubMed1977

Effect of auranofin on DNA and protein synthesis in human lymphocytes.

The effect of auranofin-a new oral gold compound for the treatment of rheumatoid arthritis-and gold sodium thiosulphate on DNA and protein synthesis, as well as their effect on membrane transport in stimulated lymphocytes was studied. It was found that only auranofin in the given concentrations inhibits the incorporation of 3H thymidine and 14C amino acids. The studies on membrane transport present evidence that the pharmacological action of auranofin might be mediated through its action at the cellular membrane level.

Arthritis, Rheumatoid↗
PubMedDate not supplied

Auranofin and sodium aurothiomalate in the treatment of rheumatoid arthritis. A double-blind, comparative multicenter study.

Auranofin (AF), a new gold compound, has been suggested as an alternative to parenteral gold in the treatment of rheumatoid arthritis (RA). This hypothesis has been tested within a double-blind comparative study and to date 103 patients have been enrolled. Forty-one RA patients have been treated for longer than 6 months. The patients were randomly allocated to treatment with either AF or sodium aurothiomalate (GSTM) and serial comparison of changes within the articular index, grip strength, pain, morning stiffness, and global assessment during treatment were measured. Improvement was noted within both treatment groups. Diarrhea as a side effect was most commonly seen during treatment with AF while rash often combined with pruritus was most commonly reported with GSTM; withdrawal from treatment as the result of this was nevertheless uncommon.

Arthritis, Rheumatoid↗
PubMed1992

A 1.4-nm gold cluster covalently attached to antibodies improves immunolabeling.

A large gold cluster (Au1.4nm) was covalently coupled to IgG and Fab' fragments. Its gold core is 1.4 nm in diameter and the Fab'-Au1.4nm immunoconjugate is the smallest gold immunoprobe that can be seen directly in the conventional electron microscope. It is useful in high-resolution immunolabeling, providing a resolution of 7.0 nm. The cluster's visibility can be enhanced with silver development for use in EM or light microscopy for histological purposes, or to detect less than or equal to 0.2 pg of antigen in immunoblots. By using a gold compound with covalent attachment, a number of advantages over colloidal gold probes are realized, including better resolution, stability, uniformity, sensitivity, and complete absence of aggregation; its small size should also improve penetration and more quantitative labeling of antigenic sites.

Animals↗
PubMedDate not supplied

Rhodium, iridium, copper and gold antitumor organometallic compounds (review).

Recent results on the antitumor activity of organometallic compounds of rhodium, iridium, copper and gold are reviewed. Coordination compounds of some organic ligands are also briefly mentioned. The most promising seem to be copper and gold complexes which exhibited remarkable activity against several tumor systems.

Animals↗
PubMed1987

Serum gold concentrations during treatment with auranofin.

Serum gold concentrations were measured in rheumatoid arthritis patients during chronic treatment with the orally adsorbable gold compound auranofin. In agreement with data in the literature, the highest serum gold concentration was reached after 16 weeks of treatment with 6 mg auranofin daily. A striking finding in this study was that thereafter the serum gold concentrations did not appear to plateau but declined gradually. Statistically this resulted in a significantly lower concentration after one year as compared with week 16 (p less than 0.05, paired t-test). It is suggested that a shift from protein bound gold to cell-bound gold might be the explanation.

Adult↗
PubMed2001

[Molecular mechanisms of action of gold in treatment of rheumatoid arthritis--an update].

Gold was first used 90 years ago by Robert Koch for the treatment of tuberculosis based on the assumption that rheumatoid arthritis was caused by microbacteria. It soon became clear that this would not explain the action of gold in rheumatoid arthritis, and since then scientists have been struggling to elucidate the mechanisms of gold's action in the treatment of rheumatic diseases. In nearly every area of immunology inhibiting actions of gold could be documented; however, it is still unclear if there is a common denominator or if there are parallel modes of actions which are independent of each other. In any case, also based on recent studies the reactivity of gold compounds with thiol groups appears to the predominant factor. Analyzing the actions of gold in the different phases of an immune reaction suggested that gold plays an important role already in the initiation, namely the uptake and presentation of foreign antigens. Thus, gold is taken up by the macrophages and stored in the lysosomes which are called aureosomes where gold inhibits antigen processing. Especially peptide antigens, which contain sulfur such as cysteine and methionine, are important. Moreover, it could be shown that gold suppresses NF-kappa B binding activity as well as the activation of the I-kappa B-kinase. This mechanism results in a subsequently reduced production of pro-inflammatory cytokines, most notably TNF-alpha, interleukin-1 and interleukin-6. On the subsequent T-cell level, gold has been shown to induce an upregulation of IL-4 mRNA, resulting in a shift of the T-cell population to the Th2 phenotype. Moreover, the activation of T-cells is inhibited. On the effector level, gold inhibits proteolytic enzymes and can result in the destruction of synovial fibroblasts. In conclusion, gold remains one of the most fascinating antirheumatic drugs with multiple modes of actions. The future analysis of molecular mechanisms, especially with regard to signal transduction, will lead to new fundamental knowledge of gold action, possible allowing a further understanding of the pathogenesis of rheumatoid arthritis.

Antigen Presentation↗
PubMed1975

Distribution of various labeled thioglucoses in rodents.

Gold, silver and lead thioglucose were evaluated in rodents to determine the value of organo-metallic compounds in the study of metabolic abnormalities. Increased radioactivity concentration was noted in the hypothalamus with all compounds. Gold thioglucose concentrated in the kidneys and thymus, and 203Pb-thioglucose concentrated in the pancreas and thymus.

Adrenal Glands↗
PubMed1985

Therapeutic uses of trace elements.

The properties of trace elements which feature in their therapeutic activity are: binding to macromolecules (enzymes, nucleic acids, etc.) with disturbance of biological function, and interaction with other elements. These properties, particularly the binding to large molecules, are far from specific, an observation which is reflected in the very wide range of diseases in which trace elements are employed. While metal compounds have been administered for several centuries, the scientific basis for treatment with trace elements began with the use of gold compounds, initially in patients with tuberculosis and later those with rheumatoid arthritis. Although many other drugs have been developed, some of which also include metal complexes, gold has retained an important position in the treatment of this condition. The gold-induced effects upon the immunological aspects of RA are also observed in other conditions with autoimmune involvement. The antineoplastic potential of metal complexes will be further exploited by the development of less toxic compounds--of platinum and possibly also of other metals. At the same time there are improvements in the protocols for administration which increase the range of cancers responding to treatment. Perturbation of gastrointestinal activity represents another area where trace elements have an important therapeutic role, both in the control of intraluminal acidity and in the adjustment of nutrient availability. A fourth significant area of trace element therapeutics involves the central nervous system where the use of lithium has provided spectacular results in the treatment of affective and other disorders. With a very wide range of other conditions in which they are employed, therapeutic uses provide somewhat unusual illustrations of the importance of trace elements in human disease.

Arthritis, Rheumatoid↗
PubMed1987

Gold therapy and its indications in dermatology. A review.

Gold compounds have long been known as therapeutic agents and have been used extensively in the treatment of rheumatoid arthritis. Their mechanisms of action in vivo, however, remain unclear. In comparison to parenteral gold, the pharmacokinetics of a newly available oral compound, auranofin, differ greatly. Auranofin also appears to have specific immunomodulatory actions and to be associated with fewer and milder toxic effects. The role of chrysotherapy in dermatology has been reemphasized recently. It may be used as an adjuvant in pemphigus or other steroid-responsive diseases to help control disease activity and to taper or eliminate corticosteroid therapy more rapidly. Reports on the use of gold in dermatology are otherwise limited. They include one case of epidermolysis bullosa acquisita and psoriatic arthritis. The benefits of gold treatment have to be weighed against the risks inherent in its adverse reactions, some of which are serious and unpredictable.

Gold↗
PubMed1992

[Possible role of cellular immunity against tubular basement membrane antigen (TBM) in gold nephropathy in rheumatoid arthritis patients].

Autoantibody formation and lymphocytes proliferative response to tubular basement membrane (TBM) antigen were examined to clarify the pathogenesis of gold nephropathy, in rheumatoid arthritis patients. The existence of tubulopathy was ascertained by urine protein analysis, electrophoresis and urine TBM antigen titration. Circulating antibody to human TBM antigen titrated by enzyme immunoassay was significantly elevated in patients with gold tubulopathy, and mitogenic stimulation with TBM antigen of peripheral lymphocytes specifically responded in the early stage after receiving gold, but then clearly decreased after the cessation of gold. But, when the lymphocytes had been passed through a nylon wool column, the reaction was remarkably high even in the later stage after receiving gold, suggesting that another suppressive population of lymphocytes became trapped in the nylon wool column. This evidence suggests that gold compounds definitely act as initiating and promoting agents, and the development of tubular disorders induced by gold are likely related to the cellular recognition of effector T cells to the TBM antigen, following the strong effect of gold on the cellular immune system.

Adult↗
PubMed1981

Localization of gold in biological tissue. A photochemical method for light and electronmicroscopy.

A detailed description is given of a method by which gold can be visualized in frozen, paraffin and Epon sections. Histological sections from animals treated with gold compounds are exposed to UV-light from 30 min to several hours. The reduced, metallic gold is then visualized by means of a photographic developer containing silver lactate. Light- and electronmicroscope photographs showing gold in different organs from rats and mice treated with aurothioglucose, aurothiosulfate and aurothiomalate are presented.

Animals↗
PubMed2000

New frontiers in gold labeling.

Recent advances in gold technology have led to probes with improved properties and performance for cell biologists: higher labeling density, better sensitivity, and greater penetration into tissues. Gold clusters, such as the 1.4-nm Nanogold, are gold compounds that can be covalently linked to Fab' antibody fragments, making small and stable probes. Silver enhancement then makes these small gold particles easily visible by EM, LM, and directly by eye. Another advance is the combination of fluorescent and gold probes for correlative microscopy. Chemical crosslinking of gold particles to many biologically active molecules has made possible many novel probes, such as gold-lipids, gold-Ni-NTA, and gold-ATP.

Gold↗
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↗
PubMed2004

Gold complexes inhibit mitochondrial thioredoxin reductase: consequences on mitochondrial functions.

The effects of gold(I) complexes (auranofin, triethylphosphine gold and aurothiomalate), gold(III) complexes ([Au(2,2'-diethylendiamine)Cl]Cl(2), [(Au(2-(1,1-dimethylbenzyl)-pyridine) (CH(3)COO)(2)], [Au(6-(1,1-dimethylbenzyl)-2,2'-bipyridine)(OH)](PF(6)), [Au(bipy(dmb)-H)(2,6-xylidine)](PF(6))), metal ions (zinc and cadmium acetate) and metal complexes (cisplatin, zinc pyrithione and tributyltin) on mitochondrial thioredoxin reductase and mitochondrial functions have been examined. Both gold(I) and gold(III) complexes are extremely efficient inhibitors of thioredoxin reductase showing IC(50) ranging from 0.020 to 1.42 microM while metal ions and complexes not containing gold are less effective, exhibiting IC(50) going from 11.8 to 76.0 microM. At variance with thioredoxin reductase, auranofin is completely ineffective in inhibiting glutathione peroxidase and glutathione reductase, while gold(III) compounds show some effect on glutathione peroxidase. The mitochondrial respiratory chain is scarcely affected by gold compounds while the other metal complexes and metal ions, in particular zinc ion and zinc pyrithione, show a more marked inhibitory effect that is reflected on a rapid induction of membrane potential decrease that precedes swelling. Therefore, differently from gold compounds, the various metal ions and metal complexes exert their effect on different targets indicating a lower specificity. It is concluded that gold compounds are highly specific inhibitors of mitochondrial thioredoxin reductase and this action influences other functions such as membrane permeability properties. Metal ions and metal complexes markedly inhibit the activity of thioredoxin reductase although to an extent lower than that of gold compounds. They also inhibit mitochondrial respiration, decrease membrane potential and, finally, induce swelling.

Animals↗
PubMed1989

Cholestasis and pneumonitis induced by gold therapy.

The authors describe the association of gold salt-induced cholestasis and lymphocytic alveolitis proved by liver biopsy and broncho-alveolar lavage. To our knowledge this is the third case report on the combination of liver disease and pulmonary infiltration induced by gold compounds.

Aged↗
PubMed2005

Gold nanocluster formation using metallothionein: mass spectrometry and electron microscopy.

Clonable contrasting agents for light microscopy, such as green fluorescent protein, have revolutionized biology, but few such agents have been developed for transmission electron microscopy (TEM). As an attempt to develop a novel clonable contrasting agent for TEM, we have evaluated metallothionein, a small metal-binding protein, reacted with aurothiomalate, an anti-arthritic gold compound. Electro spray ionization and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry measurements show a distribution of gold atoms bound to individual metallothionein molecules. Unlike previous reports, these data show gold binding occurred as the addition of single atoms without retention of additional ligands. Moreover, under certain conditions, MALDI spectra show gold binding ratios of greater than 1:1 with the cysteine residues of metallothionein. Together, this may hint at a gold-binding mechanism similar to gold nanocluster formation. Finally, metallothionein-gold complexes visualized in the TEM show a range of sizes similar to those used as current TEM labels, and show the potential of the protein as a clonable TEM label in which the gold cluster is grown on the label, thereby circumventing the problems associated with attaching gold clusters.

Gold↗
PubMed1993

Metal compounds in therapy and diagnosis.

There is increasing interest in the use of metal-containing compounds in medicine. This review describes several therapeutic applications, such as the use of platinum complexes in cancer chemotherapy, gold compounds in the treatment of arthritis, gallium in hypercalcemia, bismuth in anti-ulcer medication, and sodium nitroprusside in hypertension. The use of metal radionuclides in diagnosis and radiotherapy and the role of paramagnetic metal complexes as contrast agents in magnetic resonance imaging are also discussed.

Anti-Ulcer Agents↗