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PubMed1984

Oral gold in arthritis.

There are few drugs available with purported disease-modifying or healing effects in rheumatoid arthritis. The two agents that have gathered the most support in favor of these effects are parenteral gold and cyclophosphamide; however, both can produce intolerable toxicity. A new oral gold compound (auranofin; Ridaura) is being investigated in rheumatoid arthritis. Available studies suggest that auranofin may be slightly less effective than parenteral gold, but is significantly less toxic, the main side effect being diarrhea. There is evidence to suggest auranofin slows radiologic progression of the disease, but further studies are indicated. If further studies demonstrate a healing effect of the drug, comparable with data suggesting this effect for parenteral gold, auranofin may become a first-line agent in rheumatoid arthritis.

Administration, Oral↗
PubMed2006

A novel small-molecule inhibitor of protein kinase Ciota blocks transformed growth of non-small-cell lung cancer cells.

We recently showed that atypical protein kinase Ciota (PKCiota) is required for transformed growth of human non-small-cell lung cancer (NSCLC) cells by activating Rac1. Genetic disruption of PKCiota signaling blocks Rac1 activity and transformed growth, indicating that PKCiota is a viable target for development of novel therapeutics for NSCLC. Here, we designed and implemented a novel fluorescence resonance energy transfer-based assay to identify inhibitors of oncogenic PKCiota signaling. This assay was used to identify compounds that disrupt the interaction between PKCiota and its downstream effector Par6, which links PKCiota to Rac1. We identified aurothioglucose (ATG), a gold compound used clinically to treat rheumatoid arthritis, and the related compound, aurothiomalate (ATM), as potent inhibitors of PKCiota-Par6 interactions in vitro (IC(50) approximately 1 micromol/L). ATG blocks PKCiota-dependent signaling to Rac1 and inhibits transformed growth of NSCLC cells. ATG-mediated inhibition of transformation is relieved by expression of constitutively active Rac1, consistent with a mechanism at the level of the interaction between PKCiota and Par6. ATG inhibits A549 cell tumor growth in nude mice, showing efficacy against NSCLC in a relevant preclinical model. Our data show the utility of targeting protein-protein interactions involving PKCiota for antitumor drug development and provide proof of concept that chemical disruption of PKCiota signaling can be an effective treatment for NSCLC. ATG and ATM will be useful reagents for studying PKCiota function in transformation and represent promising new agents for the clinical treatment of NSCLC.

Adaptor Proteins, Signal Transducing↗
PubMed1987

Auranofin-associated colitis and eosinophilia.

Gold compounds, often used in the treatment of rheumatoid arthritis, have been associated with gastrointestinal disturbances in some patients. Use of auranofin, an oral gold preparation, in a 50-year-old woman with rheumatoid arthritis resulted in diarrhea, abdominal tenderness, nausea, and vomiting, which persisted despite discontinuation of auranofin therapy. The presumptive diagnosis was gold-induced colitis and eosinophilia. Administration of cromolyn sodium provided relief. Although this complication may be rare, evolving bowel symptoms in patients receiving auranofin demand prompt attention.

Arthritis, Rheumatoid↗
PubMed1988

Association of HLA-B35 with mucocutaneous lesions in Israeli patients with rheumatoid arthritis receiving gold treatment.

Seventy-four Israeli patients with rheumatoid arthritis (RA) were studied for possible association between HLA antigens and adverse reactions to gold treatment (aurothioglucose). HLA-B35 was significantly increased in patients who developed gold induced mucocutaneous lesions. These results are in accord with earlier reports, despite the different genetic background of the Israeli RA population and the different type of gold compound used.

Arthritis, Rheumatoid↗
PubMed1992

Mechanisms of action of disease modifying antirheumatic drugs.

The relationship between the biologic activities of disease modifying antirheumatic drugs (DMARD) and their therapeutic effects are complex. Some DMARD are prodrugs, e.g., azathioprine; others may act in combination with endogenous substances, e.g., D-penicillamine and copper salts. Gold compounds, antimalarials, sulfasalazine, azathioprine and methotrexate affect various phagocytic cell functions. Most DMARD inhibit the immune responses of monocytes and of T and B lymphocytes. Gold, sulfasalazine, D-penicillamine also affect fibroblast and/or endothelial cell proliferation. Many DMARD inhibit responses to, or production of, cytokines. Several DMARD have overlapping biologic effects but differ in their therapeutic efficacy in individual patients for unknown reasons.

Anti-Inflammatory Agents↗
PubMed1988

Accumulation and toxicity of gold in the rabbit lens in vitro.

Gold compounds are used therapeutically and have been observed to accumulate in the human eye. In the present study, we have measured the accumulation and loss of gold (AuIII) in rabbit lenses in vitro using 195Au as a tracer. Accumulation increased progressively with time of incubation up to 24 hr. The highest concentration of Au3+ observed was about 16 mumol kg-1 wet wt. Rate of accumulation also rose with increase in the external concentration of Au3+, but the magnitude of the change exceeded the concentration difference. Autoradiography showed a high accumulation of 195Au in a central region of the anterior face of the lens, as has been observed in vivo in humans undergoing chrysotherapy. Loss (efflux) of accumulated 195Au was increased by the presence of Au3+ or dithiothreitol in the external media. Lanthanum (La3+), however, decreased the loss of such Au and promoted its accumulation. Gold can have a toxic effect on lenses as incubation for 7 days in a medium containing 10(-7) M Au3+ resulted in a marked gain of Na and loss of K. The results suggest that Au accretion occurs at surface sites associated with the anterior of the lens, but whether or not intracellular accumulation occurs is not clear. This Au, in excess, may have toxic effects on the tissue.

Animals↗
PubMed1979

Gold-induced changes in the morphology and functional capabilities of human monocytes.

The capacity of gold compounds to induce morphologic changes and alterations in the functional activity of human mononuclear phagocytes (M phi) in vitro was examined. Human peripheral blood mononuclear cells were incubated with gold sodium thiomalate (25 microgram/ml) for 96 hours. As a result, M phi developed electron dense precipitates within phagolysosomes, as well as marked dilatation of these organelles. Gold incubation also altered a number of M phi functions. While viability and adherence were unaffected, the capacity to spread on surfaces was diminished. Pinocytosis of soluble proteins and phagocytosis of opsonized sheep erythrocytes were impaired, but Fc mediated particle binding was not. These data indicate that gold can alter certain functional activities of M phi and support the idea that the major action of gold in rheumatoid arthritis results from its capacity to alter M phi function.

Cell Adhesion↗
PubMed1999

Synergistic inhibition of human B cell activation by gold sodium thiomalate and auranofin.

The mechanism of action of gold compounds, which are effective in the treatment of rheumatoid arthritis (RA), has not been clearly identified. Since one of the characteristic features of RA is chronic stimulation of B cells, the current studies compared the effects of parenteral gold (gold sodium thiomalate; GST) and orally active gold (auranofin; AUR) on human B cells. IgM production was induced from highly purified B cells obtained from healthy donors by stimulation with Staphylococcus aureus Cowan I (SA) plus IL-2. T cell proliferation and IFN-gamma production was induced from highly purified T cells by stimulation with immobilized mAb to CD3. AUR as well as GST suppressed B cell IgM production at much lower concentrations than those that suppressed T cell proliferation or IFN-gamma production. Thus, as little as 0.01 microg/ml AUR (0.015 microM) markedly suppressed IgM production, but neither T cell proliferation nor IFN-gamma production. AUR as well as GST is required at the initiation of cultures to exert optimal suppressive effects on IgM production. Moreover, AUR as well as GST suppressed the expression of CD98 and CD71 on SA-stimulated B cells. Of note, AUR and GST exerted a synergistic inhibitory effect on B cell production of IgM and IgG in a manner which was reversed by catalase, but not by ascorbate. The synergistic inhibitory effect is most likely to be due to thiomalate components of GST, since AUR and thiomalate exerted comparable synergistic inhibitory effects on B cell function. Finally, AUR and bucillamine, another antirheumatic drug with thiol groups, also showed synergistic inhibition of B cell function. These results indicate that AUR and GST preferentially inhibit the function of B cells by interfering with the initial activation of B cells. More importantly, the data indicate that AUR synergizes with GST or thiols to inhibit B cell function in a manner that depends upon the generation of hydrogen peroxide. These synergistic inhibitory effects of AUR and compounds with thiols on in vitro human B cell activation suggest the therapeutic efficacy of combinations of these compounds in RA.

Auranofin↗
PubMedDate not supplied

No significant effects of sodium aurothiomalate on haem metabolism and mixed function oxygenase activity in patients with rheumatoid arthritis.

OBJECTIVE: Animal studies suggest that gold compounds impair haem synthesis and increase haem degradation and, as a result, reduce activity of the hepatic haemoproteins cytochromes P-450. The aim of this study was to investigate whether intramuscular gold exerts similar effects in patients with rheumatoid arthritis (RA). METHODS: Urinary porphyrin and precursor excretion, erythrocyte protoporphyrin, and antipyrine clearance, were measured in 6 patients with RA before and 10 weeks after commencement of intramuscular gold. RESULTS: Parameters of haem metabolism were unaffected by gold. While antipyrine clearance was not statistically changed after gold treatment, in 3 of the patients there was an average decrease in antipyrine clearance of 23%. CONCLUSION: Further studies examining RA patients at different time points are required to investigate further the possibility of reduced hepatic drug metabolising activity during prolonged treatment with gold.

Adult↗
PubMed1979

In vitro binding and pharmacokinetics of gold salts in plasma proteins and chelating agents.

The binding of sodium aurothiomalate, sodium aurothiosulphate and aurothioglucose to plasma proteins has been investigated in vitro. All gold compounds were bound to protein at a similar rate and had similar apparent affinity constants and binding capacities. Penicillamine (10 or 100 microgram/ml) was unable to chelate significant amounts of bound gold from plasma protein.

Aurothioglucose↗
PubMed1986

Metallothionein turnover in mammalian cells. Implications in metal toxicity.

Metallothioneins are low molecular weight, cysteine-rich proteins believed to participate in metal detoxification. Turnover of Cd-, Zn-, and Au-induced metallothionein was studied in a Chinese hamster ovary cell line which was resistant to Cd and the Au-containing drug auranofin. Cd, Zn, and Au were potent inducers of metallothionein mRNA and resulted in accumulation of approximately equal amounts of mRNA. Pulse-chase studies with [35S]cysteine revealed that the half-life of Au-, Zn-, and Cd-induced metallothionein was 0.75, 10, and 24 h, respectively. The differences in the half-life of metallothionein may be related to the tertiary structure of metal-metallothionein complexes. These results have implications in the mechanism of resistance to gold compounds.

Animals↗
PubMed1992

Gold complexes and activation of human polymorphonuclear leukocytes. Dissociation of changes in membrane potential and oxidative burst.

The effects of the gold compounds on the alteration of membrane potential of polymorphonuclear leukocytes (PMN) in response to various stimulants have been compared with their effects on the oxidative burst. The present studies have shown that gold complexes [auranofin (AF), aurothiomalate (Autm), aurocyanide (Au(CN)2-)] have contrasting effects on the membrane potential of 3,3'-dipentyloxacarbocyanine [di-O-C5(3)] loaded PMN. Au(CN)2- at concentrations which inhibit the oxidative burst of PMN did not affect the membrane depolarization after activation of PMN by phorbol myristate acetate (PMA) and N-formyl-methionyl-leucyl phenylalanine (FMLP); Autm slightly stimulated the oxidative burst but had no effect on the depolarization of PMN. In contrast, AF inhibited the depolarization of stimulated PMN to an extent depending upon the concentration of AF, the time of preincubation and the stimulus. The membrane depolarization of PMN caused by PMA, FMLP and concanavalin A (ConA) was inhibited by AF (5 microM) but the depolarization induced by calcium ionophore (A23187) was not affected. AF at the same conditions inhibits the oxidative burst of PMN induced by all these single stimuli including the calcium ionophore. Dissociation of membrane depolarization and superoxide generation caused by AF was also seen in PMN activated by two stimuli. AF (5 microM) had little initial inhibitory effect on the oxidative burst of PMN stimulated by combinations of PMA and ConA or PMA and FMLP whereas it almost totally blocked the depolarization caused by these combinations. Preincubation of cells with 5 microM AF for less than 5 min prior to the addition of PMA allowed membrane depolarization which was followed rapidly by repolarization. None of the gold complexes studied had any effect on the resting membrane potential of PMN.

Auranofin↗
PubMed1985

Ocular chrysiasis.

Thirty-four patients who had received over 1 gram of gold compounds for rheumatoid arthritis were examined for ocular chrysiasis. Ninety-seven percent of the patients receiving continuous chrysotherapy at the time of their ocular examination exhibited corneal chrysiasis. With few exceptions, corneal gold deposits were limited to the posterior one-half of the corneal thickness. Deposits tended to concentrate inferiorly and to spare the superior and peripheral cornea. Duration of chrysotherapy correlated positively with the clinically graded density of deposits. In this series, 55% (16/29) of these patients receiving gold therapy for three years or more had lenticular chrysiasis, although this has previously been considered rare. Our data suggest that gold is deposited in the cornea and lens from the anterior chamber aqueous fluid.

Adolescent↗
PubMedDate not supplied

Oral chrysotherapy in rheumatoid arthritis: minimum effective dose.

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.

Administration, Oral↗
PubMed1997

Gold: an allergen of growing significance.

Gold moved into the limelight of medical literature thanks to the anti-inflammatory activity and effectiveness of gold compounds in the treatment of rheumatoid arthritis, but more recently also because of the growing incidence of hypersensitivity induced by it which is expressed in cutaneous and mucosal reactions. This review discusses dermatotoxicity associated with gold. In some countries gold has moved into second place as allergen, following nickel. Such recognition is mainly due to improved diagnostic methods and to its inclusion in routine dermal patch testing. Some unconventional manifestations of hypersensitivity are associated with use patterns which involve intimate contact with the metal as a component of jewelry. In-depth analysis of the growing number of cases of allergy has revealed various immunological idiosyncrasies as being characteristic of this metal. These include late reactions to challenge, extraordinary persistence of clinical effects, formation of intracutaneous nodules and immunogenic granuloma unresponsive to conventional steroid therapy, the occurrence of eczema at sites distant from the site of contact, and flare-ups of eczema upon systemic provocation with allergen which are characteristic of drug induced allergy. These manifestations demand investigations at the molecular level of the unusual mechanisms of action involved.

Allergens↗
PubMed1976

A multicentre controlled trial of the effects of different dosage of gold therapy, followed by a maintenance dosage.

In a combined clinical trial with gold in patients with rheumatoid arthritis (RA) 95 patients were treated with a high initial dosage of 2,500 mg aurothioglucose in 21 weeks. Afterwards 48 of these patients received a maintenance dosage of gold and 47 patients placebo injections. Another group of 101 patients received 1,000 mg gold in 21 weeks. Finally a maintenance dose of gold was administered to 49 of these patients, to the other 52 patients placebo injections were administered. For the treatment of RA a high dosage of a gold compound offers no advantage over a low dosage. After a high dosage one can expect a significantly higher number of side effects. The development of toxicity does not influence the ultimate results. A second course of gold has hardly any benificial effect. Prolonged administration of gold is usually well-tolerated; whether it has substantial and sustained therapeutic value remains dubious. Progression of radiological abnormalities can be observed at the same moment that signs and other symptoms of the disease show improvement.

Adult↗
PubMed1999

Hypersensitivity to gold in gold sodium thiomalate-induced dermatosis.

Gold compounds are widely used in the treatment of rheumatoid arthritis. Mucocutaneous side-effects leading to the discontinuation of medication are common with these drugs. We investigated whether allergic mechanisms are involved in dermatosis induced by gold sodium thiomalate (GSTM). Thirteen gold dermatosis patients, 15 arthritis patients without any side-effects from GSTM and 11 healthy controls participated in the study. Venous blood lymphocytes from these subjects were cultured with GSTM and gold sodium thiosulphate (GSTS) in the lymphocyte proliferation test (LPT). In some cases, interferon-gamma-producing cells were enumerated in vitro (T-cell ELISpot). The subjects were also patch-tested with GSTM and GSTS. The LPT to either GSTM, GSTS or both was positive in 12 of 13 patients with gold dermatosis. In the arthritis patient group without side-effects from gold, the LPT gave two false-positive results and in the healthy control group the LPT was falsely positive with one subject. T-cell ELISpot was positive in four of six gold dermatosis patients and negative in the arthritis and healthy control groups. Only one patient who also developed contact dermatitis from gold jewellery was positive to gold in the patch test. These results indicate that gold dermatosis is mediated, at least in part, by allergic mechanisms and that the LPT is of value in the diagnosis of gold dermatosis.

Adult↗
PubMed1985

Injectable gold dermatitis and proteinuria: retreatment with auranofin.

Seven female patients with classical rheumatoid arthritis (RA), treated successfully with injectable gold salts (Fosfocrisolo ICI, 0.10 g/week, with a serum gold concentration of 200-400 mcg/dl), experienced severe gold side-effects after 3 to 20 months of therapy, requiring their withdrawal from gold despite the good results in both clinical and laboratory findings. Four patients showed mucocutaneous side-effects (2 dermatitis and 2 stomatitis) and three a moderate or severe proteinuria. Renal biopsy was performed in these patients, with a histological picture of membranous glomerulonephritis referable to gold therapy. Remission inducing drug (R.I.D.) therapy being mandatory in patients with a chronic progressive disease, and in view of the previous efficacy of gold salts, the patients were put on oral gold, Auranofin being administered 3 mg b.i.d. Both the mucocutaneous side-effects and the proteinuria ameliorated within 2 to 6 months, and the remission of the disease was maintained. The chemical and pharmacokinetic differences between the above two gold compounds are discussed.

Adult↗