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PubMed2002

New potent inhibitors of aquaporins: silver and gold compounds inhibit aquaporins of plant and human origin.

Silver and gold compounds were tested as potential inhibitors of aquaporins of plant- and human origin. Silver as AgNO(3) or silver sulfadiazine inhibited with high potency (EC(50) 1-10 microM) the water permeability of the peribacteroid membrane from soybean (containing Nodulin 26), the water permeability of plasma membrane from roots (containing plasma membrane integral proteins), and the water permeability of human red cells (containing aquaporin 1). Gold as HAuCl(4) was less effective but still inhibited peribacteroid membrane water permeability (EC(50)=10 microM). Silver and gold are more potent inhibitors of aquaporins than the presently widely used mercury containing compounds.

Aquaporin 1↗
PubMed1995

Inhibition of the DNA-binding activity of NF-kappa B by gold compounds in vitro.

Nuclear factor kappa B (NF-kappa B) is a transcription factor that is critical for the inducible expression of multiple cellular and viral genes. DNA binding activity is essential for its function. Here, we report that gold compounds, especially aurothioglucose (AuTG), have a strong inhibitory effect on NF-kappa B-DNA binding. Our finding also reveals that Zn2+ is a necessary component of NF-kappa B for its DNA binding activity and that gold ion can efficiently block NF-kappa B-DNA binding, presumably through oxidation of the cysteins associated with zinc. This redox mechanism may provide an explanation for the observed efficacy of gold compounds in the treatment of rheumatoid arthritis.

Aurothioglucose↗
PubMed2005

Bronchiolar disease associated with gold compounds administration in a patient with rheumatoid arthritis.

We report the case of a female patient with rheumatoid arthritis (RA) treated with gold sodium thiomalate and auranofin who developed bronchopulmonary involvement. Chest X-ray films showed diffuse mottled infiltrates and bronchial wall thickness in both lungs. Computed tomography revealed opacities along the thickening of the bronchovascular bundles. The pathologic findings were indistinguishable from those of diffuse panbronchiolitis. After discontinuation of gold compounds and initiation of steroid administration, her subjective symptoms immediately subsided. We conclude that our patient, who had suffered from chronic sinusitis and had a predisposition to bronchiolar disease, had bronchiolar disease induced by gold compounds.

Journal Article↗
PubMed1976

Auranofin. New oral gold compound for treatment of rheumatoid arthritis.

Eight patients with rheumatoid arthritis were treated with SK & F D-39162 (auranofin), a new oral gold compound which was effective in suppressing adjuvant-induced arthritis in rats. Clinical and humoral parameters were studied during a 3-month period of drug administration followed by a 3-month period under placebo. The drug was absorbed, well tolerated, and its action was manifested by a drop in the mean IgG blood levels in the third week of treatment accompanied by clinical improvement after 5 weeks of oral gold intake. Together with IgG changes, an increase of the albumin ratio was observed, as well as a decrease of alpha2-globulin and rheumatoid factor titres. From a total number of 60 swollen joints found initially in the 8 patients only 17 were swollen at week 12 and 9 at week 15. Although the number of patients treated was too small to allow definite conclusions, a follow-up study under placebo of clinical and laboratory changes in the same patients during another 3-month period showed that IgG serum levels rapidly reverted preceding a flare up of disease activity after withdrawal of the drug. This confirmed a direct role in cause-effect relation played by the new oral gold compound.

Adult↗
PubMed1992

[Gold compounds and D-penicillamine for therapy of rheumatoid arthritis].

Rheumatoid arthritis is a severe disease and it is difficult to prevent the progression of disease. Gold compounds (injectable gold and oral gold) and D-penicillamine (D-PA) have the possibility to retard joint destruction and to slow radiological progression. These drugs are called Disease Modifying Antirheumatic Drugs (DMARD), and they should be tried in cases resisting conventional NSAID's therapy. They are effective in more than 60% in severe rheumatoid patients but they also have many side effects, e.g. eczema, skin rash, renal dysfunction, aplastic anemia. Laboratory checks should be carried out once a month during the first six month, and every 2 or 3 months thereafter. To compare injectable gold with D-PA, discontinuation due to inefficacy of D-PA is higher than with injectable gold, but side effects of injectable gold is greater. Oral gold is less effective than the other 2 drugs, but has a lower rate of side effects.

Arthritis, Rheumatoid↗
PubMed1983

Effects of gold compounds on the function of phagocytic cells. II. Inhibition of superoxide radical generation by tripeptide-activated polymorphonuclear leukocytes.

The effect of sodium aurothiomalate and triethylphosphine gold on the generation of superoxide radicals by chemotactic tripeptide-activated polymorphonuclear leukocytes has been investigated using a cytochrome C reduction technique. Neither gold compound inhibited the binding of the tripeptide to cells. Sodium aurothiomalate in concentrations ranging from 1 to 100 micrograms/ml produced mild, nonsignificant inhibition of the generation of superoxide radicals. In contrast, triethylphosphine gold at a concentration of 0.25 microgram/ml was associated with a mild enhancement of superoxide radical production, but the enhancement was not statistically significant. At concentrations of 1.25 micrograms/ml and above, there was a profound inhibition of superoxide radical production by these activated cells. Since the products of the respiratory burst, including superoxide, are thought to be inflammatory mediators, it is postulated that the inhibition of superoxide radical generation by gold compounds may be another mechanism by which the compounds modulate their antiinflammatory effects in patients with rheumatoid disease.

Binding Sites↗
PubMed1984

Gold compounds in rheumatic diseases--2.

Though many basic questions on the mechanism of action, dosage schedules, and long-term efficacy remain to be answered, gold therapy still plays a major role in the treatment of rheumatic diseases. Continuous, rather than intermittent, treatment with intramuscularly administered gold compounds is now recommended, though treatment terminations due to side-effects or lack of efficacy are relatively high in the long term. The advent of orally administered gold preparations may herald a new approach to chrysotherapy of rheumatic conditions. However, the toxicity of gold compounds remains high and can be reduced only by the strictest monitoring schedules. Serial blood tests should be performed regularly, and any downward trend in platelet or neutrophil counts should be regarded with suspicion. Early detection of toxicity is likely to prevent the occurrence of severe side-effects.

Bone Marrow Diseases↗
PubMed1987

Induction of metallothionein is correlated with resistance to auranofin, a gold compound, in Chinese hamster ovary cells.

Metallothioneins (MTs) are low molecular weight, thiol-rich, metal-binding proteins. Auranofin (AF) is a gold compound active in the treatment of rheumatoid arthritis. The effects of AF on regulation of MT gene expression in Chinese hamster ovary cells were studied. AF-resistant cells accumulated substantial amounts of MT mRNA and protein, whereas no induction was observed in AF-sensitive cells. Cells capable of inducing MT in the presence of AF were much less sensitive to AF-mediated cytotoxicity. Induction of MT by low concentrations of Cd protected cells from subsequently administered doses of AF. The level of protection correlated with the level of induced MT. These findings indicate that MT plays a central role in the mechanisms underlying cellular resistance to gold compounds.

Animals↗
PubMed1993

Antirheumatic gold compounds and penicillamine enhance protein kinase C-mediated activation of the arachidonate-mobilizing phospholipase A2 in mouse macrophages.

The effects of antirheumatic gold compounds and D-penicillamine on protein kinase C- and Ca(2+)-mediated activation of arachidonate mobilization and the formation of eicosanoids in mouse macrophages have been investigated. Auranofin (0.2-2 microM) enhanced the response to phorbol ester two- to three-fold, and similar enhancement was caused by aurothiomalate, aurothioglucose, and penicillamine, but only after pretreatment for 1-4 h. The enhanced mobilization of arachidonate was accompanied by increased formation and release of prostaglandin E2 and 6-keto prostaglandin F1 alpha, but not of lipoxygenase metabolites. No such enhancement occurred when the arachidonate-mobilizing phospholipase A2 was activated directly (calcium ionophore A23187). Instead, auranofin caused selective inhibition of calcium ionophore-induced formation of leukotriene C4. Treatment of macrophages with 4 beta-phorbol 12-myristate 13-acetate causes a rapid increase in the phosphorylation and a 1.4-1.8-fold increase in the activity of the 85-kd arachidonate-mobilizing phospholipase A2 as determined in an in vitro assay. The increase in activity was further enhanced by both the gold compounds and penicillamine. These findings indicate that the target for the enhancing effect of the antirheumatic drugs is located between protein kinase C and phospholipase A2 in the signal chain leading to activation of the latter enzyme.

Animals↗
PubMed1981

Screening trial with the coordinated gold compound auranofin using mouse lymphocyte leukemia P388.

The coordinated gold compound, 2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranosato-S-triethylphosphine-gold (auranofin) was found to be effective in increasing the life span of C57BL x DBA/2 F1 mice inoculated with the lymphocytic leukemia P388. A number of dose schedules were used, the lowest dose being 6 mg/kg every fourth day and the highest dose being 6.0 mg/kg twice daily for 9 days; the lowest and highest doses produced treated versus control ratios of 140 and 220%, respectively. All treatment groups achieved the minimum treated versus control ratio of 125%. Animal weights remained stable at twice-daily and high-dose-daily regimens. Increased life span and weight changes were both found to correlate with drug concentration and/or dose frequency.

Animals↗
PubMed1985

Effect of two gold compounds on human polymorphonuclear leukocyte lysosomal function and phagocytosis.

Lysosomal neutral proteases, once released, are considered to play an important role in the rheumatoid inflammatory process. The effect of two gold compounds on human polymorphonuclear lysosomal enzymes was studied during reverse endocytosis. Phagocytosis was assessed using dual-labeled liposomes. Auranofin, a new antirheumatic gold compound, reduces human polymorphonuclear leukocyte phagocytoses and lysosomal elastase and beta-glucuronidase release at a therapeutically achievable concentration (5 microM). Sodium aurothiomalate was ineffective at this concentration.

Auranofin↗
PubMed2003

Gold compounds inhibit adhesion of human cancer cells to vascular endothelial cells.

Transcription factor NF-kappaB controls the expression of a number of genes including those for cell adhesion molecules such as E-selectin, ICAM-1 and VCAM-1. These cell adhesion molecules are known to play important roles in a critical step of tumor metastasis; the arrest of tumor cells on the venous or capillary bed of the target organ. NF-kappaB is activated by extracellular signals such as those elicited by the proinflammatory cytokines, TNF and IL-1. Here we demonstrate that IL-1beta induces nuclear translocation of NF-kappaB in human umbilical vein endothelial cells (HUVEC) followed by induction of cell surface expression of E-selectin, ICAM-1 and VCAM-1, and subsequently augments adhesion of cancer cells expressing sialyl Lewis antigen, a ligand of E-selectin. We also demonstrated that the adhesion of tumor cells to IL-1beta-treated HUVEC was inhibited by gold compounds such as aurothioglucose and aurothiomalate. These observations indicate the involvement of NF-kappaB in cancer metastasis and suggest the feasibility of using gold compounds to prevent metastasis.

Cell Adhesion↗
PubMed1979

Metabolism and distribution of gold compounds.

The pharmacokinetics of gold in blood and urine are compared during intramuscular and oral chrysotherapy for rheumatoid arthritis. Blood gold levels are 3 to 10 fold higher with injectable aurothioglucose and gold sodium thiomalate (50 mg/week) than with oral auranofin (6 mg/day). But, the serum half-life of the parenteral compounds is significantly shorter (5.5 days) than the oral agent (14-21 days). The gold content of urine is nearly 10 times higher with the intramuscular compounds than with the oral drug. The excretory pathways and tissue distribution of gold during conventional intramuscular chrysotherapy are reviewed. Forty percent of a 50 mg injection of gold sodium thiomalate is excreted in 7 days, of which 70% is recovered in the urine. Highest gold concentrations are found in the reticuloendothelial system, adrenal glands and kidneys, while the bone marrow, liver, skin and bone contain the greatest quantities of gold.

Animals↗
PubMed2003

Inhibition of TPA-induced NF-kappaB nuclear translocation and production of NO and PGE2 by the anti-rheumatic gold compounds.

Auranofin, aurothioglucose and aurothiomalate (10 microM each) inhibited 12-O-tetradecanoylphorbol 13-acetate (TPA, 16.2 nM)-induced nuclear translocation of nuclear factor-kappa B (NF-kappaB), and production of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) in rat peritoneal macrophages when the cells were pre-incubated with each gold compound for 20 h. Without pre-incubation for 20 h, aurothioglucose and aurothiomalate, but not auranofin, failed to inhibit the TPA-induced NF-kappaB nuclear translocation and production of NO and PGE(2). Auranofin, aurothioglucose and aurothiomalate did not affect the direct binding of NF-kappaB to the DNA probe. It was suggested that these gold compounds inhibit the TPA-induced production of NO and PGE(2) by inhibiting the NF-kappaB nuclear translocation.

Animals↗
PubMed1993

Repression of glucocorticoid receptor function by the anti-rheumatic gold compound aurothiomalate.

We describe functional interaction between the anti-rheumatic water-soluble gold compound aurothiomalate and glucocorticoid receptors. Aurothiomalate contains gold in the Au(I) state, and Au(I) alone, not thiomalate or malate, reduced the ligand-binding activity of the glucocorticoid receptor. Au(I) also interfered with the productive interaction between the glucocorticoid receptor and the cognate target DNA sequences and repressed the transactivation function of the receptor. Thus, Au(I) variably modulates glucocorticoid receptor-mediated intracellular signals.

Animals↗
PubMed1983

Superoxide radical production by human leukocytes exposed to immune complexes: inhibitory action of gold compounds.

Superoxide radicals produced by phagocytic cells are considered to be important mediators in the rheumatoid inflammation. The effect of the gold compounds auranofin (AF) and gold sodium thiomalate (GST) on superoxide production by human leukocytes was investigated in two models of immunologic injury: immune-complex phagocytosis and frustrated phagocytosis. In both systems, AF (0.5-1.0 micrograms Au/ml) showed a potent inhibitory activity on superoxide generation, quantitated by ferricytochrome c and NBT reduction. GST showed only modest inhibition at higher concentrations (100 microM). The thiol protecting agent dithiothreitol, 1 mM, completely blocks the inhibitory effect of AF. The inhibition of the oxy radical generation by AF may play an important role in the control of rheumatoid inflammation; it is suggested that this action might be mediated through sulfhydryl-AF interaction at the cellular membrane level.

Anti-Inflammatory Agents↗