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PubMed1987

Comparison of the effects of auranofin, gold sodium thiomalate, and penicillamine on resorption of cultured fetal rat long bones.

We compared three antirheumatic agents: auranofin (Aur), gold sodium thiomalate (GST), and penicillamine (Pen) for their effect on resorption in control unstimulated cultures of fetal rat long bones and in cultures stimulated by parathyroid hormone (PTH), prostaglandin E2 (PGE2), and murine interleukin-1 (mIL-1). Aur (3 X 10(-6) M) and GST (10(-4) M) inhibited PTH-stimulated bone resorption by 39 and 42%, respectively. The same concentrations of Aur and GST inhibited PGE2-stimulated bones by 72 and 44, respectively, and mIL-1-stimulated bones by 74 and 50%, respectively. Pen (10(-4) M) was not effective against any of the stimulators. Dose-response curves showed that Aur was at least 10 times more potent than GST. Inhibition by Aur was sustained after removal of the drug, while there was full recovery from GST. Aur inhibited 3H-thymidine and 3H-proline incorporation into bones, while GST had no effect. Aur and GST decreased beta-glucuronidase activity to undetectable levels at five days of culture. Part of the therapeutic effectiveness of Aur and GST may reside in their ability to inhibit periarticular destruction by inhibiting PGE2- and IL-1-mediated osteoclastic bone resorption.

Animals↗
PubMed1997

Differential influences of gold sodium thiomalate and bucillamine on the generation of CD14+ monocyte-lineage cells from bone marrow of rheumatoid arthritis patients.

An adequate supply of peripheral blood monocytes, granulocytes, and platelets is necessary for an optimal inflammatory process. We have previously demonstrated that the generation of CD14(+) monocyte-lineage cells from the bone marrow is accelerated in patients with rheumatoid arthritis (RA). The current studies examined the influences of gold sodium thiomalate (GST) and bucillamine (BUC), two potent disease-modifying antirheumatic drugs (DMARDs), on the capacity of bone marrow progenitor cells to generate CD14(+) cells in patients with RA, in order to delineate their mechanisms of action. CD14(-) cells purified from bone marrow specimens of 13 patients with active RA who were not taking DMARDs were cultured in the presence or absence of pharmacologically attainable concentrations of GST (25 microM) or intramolecular disulfide form of bucillamine (BUC-ID, 3 microM), a major metabolite of BUC. After incubation for 14 days, the cells were analyzed by flow cytometry for expression of CD14, HLA-DR, and CD54. The generation of CD14(+) cells from RA bone marrow CD14(-) progenitor cells was significantly suppressed by GST, but not by BUC-ID. The expression of HLA-DR on the bone marrow-derived CD14(+) cells was also significantly inhibited by GST, but not by BUC-ID. Of note, neither GST nor BUC-ID influenced the expression of CD54 on the bone marrow-derived CD14(+) cells, indicating that the expression of HLA-DR and CD54 on the bone marrow-derived CD14(+) cells is regulated by different mechanisms. The results are consistent with the hypothesis that one of the effects of DMARDs may involve the interference with monocyte differentiation in the bone marrow. Moreover, the data emphasize that in contrast with BUC, GST is a potent inhibitor of monopoiesis in RA patients.

Adult↗
PubMed1992

Interleukin-8 in inflammatory rheumatic diseases: synovial fluid levels, relation to rheumatoid factors, production by mononuclear cells, and effects of gold sodium thiomalate and methotrexate.

The content of interleukin-8 (IL-8) in the synovial fluid and its production by blood and synovial fluid mononuclear cells (PBMC and SFMC) was compared in rheumatoid arthritis (RA) and various other inflammatory rheumatic disorders. The study included 125 patients and 20 healthy individuals. The highest concentrations of IL-8 were found in the synovial fluids and culture supernatants of PBMC and SFMC from patients with seropositive RA. Only PBMC from seropositive patients, and not from other rheumatic diseases, exhibited significant spontaneous release of IL-8 that correlated with serum IgM rheumatoid factor titers. Gold sodium thiomalate (GST) and methotrexate (MTX) inhibited the spontaneous and stimulated IL-8 production by PBMC by 55-86% at 50 and 10 micrograms/ml, respectively. Two main conclusions were drawn: (1) rheumatoid factors appeared to be a major cause of enhanced IL-8 production in seropositive RA, and (2) inhibition of IL-8-mediated neutrophil migration and activation could be part of the mechanism of action of GST and MTX.

Anti-Inflammatory Agents↗
PubMed1978

Immunopharmacology of gold sodium thiomalate and auranofin (SK&F D-39162): effects on cell-mediated immunity.

The effects of gold sodium thiomalate (GST) and auranofin (SK&F D-39162) on cell-mediated immunity were investigated using oxazolone-induced contact sensitivity and delayed hypersensitivity to sheep red blood cells. C57Bl mice were sensitized to oxazolone on day 0 and challenged either 45 or 72 h later. The resulting paw edema was read plethysmographically 24 h after challenge. GST and auranofin both were capable of stimulating oxazollone-induced contact sensitivity which was compromised by using a shortened sensitization period (45 h). Auranofin but not GST stimulated the response to oxazolone in immunosuppressed mice, but neither agent significantly altered the uncompromised response in normal mice. The stimulatory effect of auranofin and GST on cell-mediated immunity was corroborated using SRBC to induce delayed hypersensitivity. Comparison of blood Au levels revealed that gold in the form of auranofin was approximately 4x more effective in stimulating cell-mediated immunity than was gold in the form of GST. These results were suggested to be due to the possible stimulation by gold of T effector as well as T suppressor lymphocytes, thus explaining the condition dependency of the immunoregulation.

Animals↗
PubMed1990

Induction of membrane proliferation in mouse CNS by gold sodium thiomalate with reference to increased virulence of the avirulent Semliki Forest virus.

Separation of smooth membrane vesicles from whole mouse brain by isopycnic centrifugation in discontinuous sucrose density gradients show an increased membrane proliferation in gold sodium thiomalate (GSTM) treated mice. Induction of membrane proliferation by GSTM seems to be an important factor in converting the avirulent Semliki Forest virus infection into a lethal one.

Animals↗
PubMed1998

Induction of drug resistance to gold sodium thiomalate in a monocyte cell line, THP-1.

The expression of metallothionein, an intracellular heavy-metal-binding protein, and p-glycoprotein, an energy-dependent drug efflux pump, was examined to study the mechanism of cell resistance to gold sodium thiomalate (GST). THP-1, one of the monocyte-derived cell lines, was cultured for 6 months and resistance to 25 microg/ml of GST (GST-resistant cells) was thus induced. The GST-resistant cells were then cultured with bucillamine to examine the presence of cross-resistance. The intracellular GST concentration was examined by flameless atomic absorption spectroscopy. The cell viability was determined by the uptake of 3-4,5 dimethylthiazole-2,5 diphenyl tetrazolium bromide (MTT). The expression of p-glycoprotein was detected by Western blotting using monoclonal anti-p-glycoprotein antibody. The expression of metallothionein was detected using the indirect immunofluorescence technique. GST-resistant cells did not show any cross-resistance to bucillamine. The rate of cytoplasmic GST accumulation decreased in the GST-resistant cells, while the rate of GST efflux also decreased. The expression of p-glycoprotein in the GST-resistant cells was not significantly different from that in the cells not treated with GST. On the other hand, the GST-resistant cells showed a higher expression of metallothionein than cells not treated with GST. These findings suggest that the induced resistance to GST might partly be due to an induction of metallothionein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1988

Auranofin and gold sodium thiomalate in the treatment of rheumatoid arthritis: a one-year, double-blind, comparative multicenter study.

In a 48-week, double-blind trial, 122 patients were randomly assigned to treatment with auranofin (60) and gold sodium thiomalate (GST) (62) at five centers. Both groups showed significant improvement (P less than 0.05) from baseline in parameters of disease activity. Results of the covariance analysis for all patients who completed the trial showed no significant differences (P less than 0.05) in efficacy between the two groups. The proportions of patients showing 50% or greater improvement in tender joints, swollen joints, activity index, severity of pain, general health rating, and erythrocyte sedimentation rate (ESR) were similar for both auranofin-treated and GST-treated patients who completed the 48-week trial. When all patients who entered the trial were evaluated, a slightly greater proportion of patients on auranofin had improved. Diarrhea occurred more frequently with auranofin (32%) compared to GST (19%), whereas rash and pruritus were twice as common in those patients treated with GST compared to those treated with auranofin. The withdrawal rate due to adverse reactions was 10% for auranofin vs 26% for GST. It was concluded that the efficacy of auranofin was comparable to that of injectable gold and was better tolerated, as evidenced by the lower withdrawal rate from adverse events for the auranofin patients.

Adult↗
PubMed1982

Effect of in vivo administration of gold sodium thiomalate on rat macrophage function.

It has been shown that gold accumulates in macrophages. In vitro studies have also shown that long-term anti-inflammatory and immuno-regulatory effects on these cells may be responsible for the effectiveness of gold in the treatment of rheumatoid arthritis. However, the relevance of this information to the in vivo circumstance is largely untested. In this study, the effect of gold sodium thiomalate (AuTM) on rat alveolar macrophage (AM) lysosomal enzymes, bacterial killing, and metabolic activities associated with phagocytosis were assessed after in vivo administration. The activities of beta-glucuronidase, acid phosphatase, and lysozyme were inhibited 1 day following a single AuTM injection (50 mg/kg, subcutaneous). However, lysozyme returned to normal, while the activities of beta-glucuronidase and acid phosphatase were elevated from 4 to 12 days thereafter. When AuTM was administered weekly for 8 weeks, the activities of acid phosphatase and beta-glucuronidase were elevated throughout, while lysozyme was largely unaffected. The increased lysosomal enzyme activities were not due to contamination of polymorphonuclear leukocytes. These long-term effects of AuTm on enzyme activity were in marked contrast to its in vitro effect which inhibited the activities of beta-glucuronidase and acid phosphatase. No effect of AuTM administration on the release of beta-glucuronidase upon phagocytosis of opsonized zymosan was observed. At 1 day following a single AuTM injection or 3 days after a second weekly injection, in vivo bactericidal activity of AM toward S. aureus was diminished. This bacterial killing defect was not due to decrease phagocytosis; the in vivo binding and ingestion of bacteria were normal. The defect correlated with imparied metabolic activities associated with phagocytosis, namely a significant decrease in the reduction of nitroblue tetrazolium and the stimulation of the hexose monophosphate shunt. This may be an attractive anti-inflammatory effect in light of the destructive potential of the reactive oxygen species produced by macrophages in an arthritic circumstance.

Animals↗
PubMed1991

Protective effects of chelating agents against renal toxicity of gold sodium thiomalate in rats.

The protective effects of various chelating agents such as D-penicillamine (D-PEN), 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercaptopropane sulphonate (DMPS), and N-(2-mercapto-2-methylpropanoyl)-L-cysteine (bucillamine), on the renal damage induced by gold sodium thiomalate (AuTM) in rats were studied. Rats were injected i.v. with AuTM at doses of 0.026, 0.066, 0.132, and 0.198 mmol/kg. Urinary excretion of protein, aspartate aminotransferase (AST), and glucose in rats injected with AuTM significantly increased compared to the control levels within 1 day after the injection and thereafter decreased nearly to the control levels at 3 or 7 days. Gold was excreted rapidly during the first day after AuTM injection and excreted gradually thereafter. The concentrations of gold in the kidney and liver at 1 or 7 days after AuTM administration were approximately dose dependent. Treatment with D-PEN, DMSA, DMPS, and bucillamine (1.2 mmol/kg) significantly prevented increases in the urinary excretion of protein, AST, and glucose and the BUN level after AuTM (0.026 mmol/kg) injection. The injection of the chelating agents after AuTM administration showed that D-PEN, DMSA, and DMPS enhanced mainly the urinary excretion of gold and that bucillamine enhanced mainly the fecal excretion of the metal. These chelating agents significantly decreased the gold concentrations in the kidney and liver. The findings suggest that the chelating agents tested can ameliorate the renal damage induced by AuTM.

Animals↗
PubMed1993

Effects of gold sodium thiomalate, cyclosporin A, cyclophosphamide, and placebo on collagen-induced arthritis in rats.

The prophylactic and therapeutic effects of gold sodium thiomalate, cyclosporin A, cyclophosphamide, and placebo on collagen-induced arthritis (CIA) were evaluated in DA rats. Prophylactic treatment with cyclosporin A and cyclophosphamide suppressed the arthritis incidence, clinical inflammation, destructive bone changes, and development of anti-collagen antibody in DA rats subsequently injected with porcine type-II collagen. Therapeutic treatment with cyclosporin A and cyclophosphamide had a definite suppression on established CIA when started 21 days after the initial collagen injection, but the suppression was less marked than that of prophylactic treatment. Gold had no impact on CIA in DA rats when administered either prophylactically or therapeutically.

Animals↗
PubMed1985

Effects of D-penicillamine, dichlofenac sodium and gold sodium thiomalate upon the selective release of lysosomal enzymes from human polymorphonuclear leucocytes to immune complex.

The selective release of beta-glucuronidase (beta-Gluc) and beta-N-acetylglucosaminidase (beta-Glm) from human polymorphonuclear leucocytes (PMN), initiated with bovine serum albumin/anti-bovine serum albumin (BSA/anti-BSA) immune complex (15 micrograms/ml-1) was significantly reduced by increasing concentrations (10(-7) M, 10(-6) M and 10(-5) M) of D-penicillamine (D-PEN) in a dose-dependent fashion. These effects upon the exocytosis of the lysosomal enzymes studied are in accordance with the results obtained previously in rats with adjuvant arthritis. In contrast, Dichlofenac Sodium (DICHL), which has been found to exert inhibitory activity upon extracellular release of beta-Gluc and beta-Glm in adjuvant arthritic rats in previous studies, had no significant in vitro effect on the exocytosis of these enzymes at the concentrations identical to those of D-PEN. Also, Gold Sodium Thiomalate (GST), in the same concentrations ranging from 10(-7) M-10(-5) M, failed to inhibit selective release of beta-Gluc and beta-Glm in the present investigations. Additionally, BSA/anti-BSA, D-PEN, DICHL and GST did not significantly produce the extracellular release of lactate dehydrogenase (LDH) indicating that under experimental conditions described the cell remained intact. Moreover, neither D-PEN, DICHL, GST or BSA/anti-BSA significantly changed the activities of lysosomal enzyme markers used in these experiments. The possible mechanism(s) of the observed phenomena are discussed.

Acetylglucosaminidase↗
PubMed1976

Effect of concurrent administration of aspirin, indomethacin or hydrocortisone with gold sodium thiomalate against adjuvant-induced arthritis in the rat.

The activity of gold sodium thiomalate (GST) given i.m. to adjuvant-induced polyarthritic rats was studied alone or in combination with active doses of aspirin, indomethacin and hydrocortisone. In addition to paw volume and body weight changes, erythrocyte sedimentation rate, serum albumin/globulin and gold levels as well as plasma activities of beta-glucuronidase, acid phosphatase, lysozyme and lactic acid dehydrogenase were measured. In prophylactic studies the beneficial activity of GST was unaffected by aspirin, suggesting a positive drug interaction, but additive with indomethacin or hydrocortisone for the 1st but not 2nd lesion of the disease. These results were closely correlated with increased serum gold levels. Similar clinical findings were observed in therapeutic studies except that a positive drug interaction occurred between GST and hydrocortisone. Unlike in the prophylactic experiments, serum gold levels were unaffected by any of the agents tested in the therapeutic studies.

Animals↗
PubMed1990

A three year comparative study of auranofin and gold sodium thiomalate in rheumatoid arthritis.

UNLABELLED: One hundred twenty-one patients with active RA were randomly assigned to receive 6 mg auranofin (AF)/day (60 patients) or 50 mg gold sodium thiomalate (GST)/week (62 patients) in a double-blind fashion. There were no intergroup differences with respect to sex, age, duration (median 2 years), stage and activity of the disease. In the case of "striking improvement" after 24 weeks a dose reduction to 50 mg GST/month or 4 mg AF/day was allowed and carried out in all GST patients and no AF patient. The serum gold levels were 5 times higher with weekly GST, they approached those of the AF group with monthly GST injections. The clinical parameters--number of swollen joints, activity index, articular index, grip strength, ESR--improved significantly in both groups, but grip strength, articular index and ESR improved more pronounced in the GST group. The X-ray progression (hands and forefeet) was significantly greater in the AF group. Forty-eight AF patients (80%) and 39 GST patients (36%) completed the first year. Thereafter the study was continued as an open study but the patients were allowed to switch from GST to AF. After the first and second year 14/7 GST patients switched to AF. The second/third year was completed by 37/22 AF pat. (62%/37%) and by 15/8 GST pat. (24%/13%). Skin reactions were more common with GST (41.9%/26.7%), diarrhoea was more common with AF (36.7%/19.4%), proteinuria occurred in 10% in both groups, leucopenia and thrombocytopenia were rare in both groups (1.7%). The withdrawal rate due to adverse events was 10%/26% in the AF/GST group during the first year (p less than 0.05) and 25%/32% over the three year period (n.s.). CONCLUSION: Both AF and GST are effective in the long-term treatment of RA, but GST is more so in radiological progression and ESR.

Arthritis, Rheumatoid↗
PubMed1994

Treatment of psoriatic arthritis with auranofin and gold sodium thiomalate.

Forty-two patients with psoriatic arthritis were included in a multicenter, double-blind trial comparing auranofin and gold sodium thiomalate (GST) for 6 months, followed by a 6-month open treatment. Fifty-two percent of the patients on auranofin and 33% on GST were able to complete the 1-year course of therapy. As a result of the study we conclude that both gold compounds are effective agents in the treatment of psoriatic arthritis. Degree of improvement of arthritis was better in the GST group, but the number of improved patients was greater in the auranofin group. Two patients on auranofin were withdrawn for side effects (one diarrhoea, one worsening of psoriasis) and 5 on GST (rash 2, total loss of appetite 1, exacerbation of psoriasis 2). Comparing the side effects of both compounds, auranofin is less likely to aggravate the psoriatic condition or result in withdrawal of patients for adverse reactions.

Adult↗
PubMedDate not supplied

Role of metallothionein in cellular uptake and disposition of gold sodium thiomalate.

Rat liver and kidney tissue uptake of gold and its localization in the cytosol was studied following various doses of gold sodium thiomalate (GST). The timecourse of gold incorporation into intracellular gold-binding ligands following repeated injections of GST was also investigated (11 injections, one dose/week). Results show that between 30 and 60% of the hepatic and renal gold was localized in the cytosol over a wide range of GST doses. This was also true following repeated doses. In the kidney, the binding of gold to high molecular weight (HMW) proteins was saturated after the third GST dose, while incorporation into the metallothioneins (MT) continued to increase, accounting for as much as 50% of cytosolic gold. On the other hand the binding to hepatic MT was about 10x lower, and the proportion of cytosolic gold incorporated into the MT, decreased from 30% (after first 3 GST injections) to about 15% (following the last 3 injections). The results show that the stimulation of MT biosynthesis in different tissues as a response to the injected GST is not the same and varies within each organ with the dose and/or the duration of repeated exposure. In the liver, the ability of gold to induce MT synthesis was limited and the importance of MT in the cellular uptake and disposition of gold may largely be confined to the kidneys. It is suggested that besides playing a possible role in the detoxification of cellular gold, particularly in the kidney, MT may also contribute towards the retention and localization of gold in the tissues.

Animals↗
PubMed1984

Auranofin, gold sodium thiomalate, and placebo in the treatment of rheumatoid arthritis. Cooperative systematic studies of rheumatic diseases.

Two hundred eight patients were studied in a prospective, controlled, double-blind multicenter trial comparing auranofin (AUR), gold sodium thiomalate (GST), and placebo. One hundred sixty-one patients completed at least 20 weeks of therapy. Response to a variety of measures of efficacy was generally modest for both gold treatment groups although improvement was continuing in both groups at the end of the study. There was statistically significant improvement with both gold preparations compared to placebo for the number of tender joints, the joint tenderness score, and physician assessment of disease severity. GST was also significantly better than placebo for the joint swelling score. GST demonstrated more improvement in patients with anemia and thrombocytosis compared to the other treatment groups and both gold preparations were superior to placebo in improvement of an elevated erythrocyte sedimentation rate. Twenty-seven percent of patients on GST were withdrawn from the study for adverse drug reaction with rash and stomatitis being the predominant cause. Only 6% of patients on AUR were withdrawn for untoward drug effect. The time of onset of the adverse reactions is discussed. The two gold preparations were similar in efficacy although AUR was better tolerated.

Anti-Inflammatory Agents↗
PubMed2000

Combination therapy with hydroxychloroquine, gold sodium thiomalate and methotrexate in early rheumatoid arthritis. An open 3-year study.

During recent years, aggressive therapeutic approaches have been proposed in order to control the Rheumatoid Arthritis (RA) activity and to avoid joint destruction. Here we report the results of an open 3-year trial on the combination of three second-line drugs, hydroxychloroquine (HCQ), methotrexate (MTX) and gold sodium thiomalate (GST), in early active RA. Four men and 17 women were enrolled in the study and were treated during the first year with HCQ 400 mg/day, GST 50 mg/week and oral MTX 7.5 mg/week; during the second and the third years the doses of HCQ and MTX were reduced to 200 mg/day and 5 mg/week, respectively; the interval between the GST injections was progressively increased until 4 weeks. Prednisone at an initial dose not higher than 10 mg/day was associated. Sulindac was allowed. Eight patients left the study because of side-effects, 2 patients abandoned the study, 12 patients compleated the 3 years of treatment. We obtained a significant and early amelioration of both clinical and laboratory parameters during the first year; in the two subsequent years the positive results were maintained. In our opinion the most significant result is the absence of anatomical progression in 10 out of 12 patients, even if a more prolonged observation is necessary to obtain more reliable data.

Adult↗