The effects of gold-containing compounds on pregnant rats and their fetuses.
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Abnormalities, Drug-Induced↗
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The effects of gold-containing compounds on pregnant rabbits and their fetuses.
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Abdomen↗
Auranofin inhibits the induction of interleukin 1 beta and tumor necrosis factor alpha mRNA in macrophages.
Gold compounds are widely used in the treatment of rheumatoid arthritis, but their mechanisms of action remain unclear. We demonstrate here that auranofin (AF) (0.1-3 microM), but neither the hydrophilic gold compounds aurothiomalate (ATM) and aurothioglucose nor methotrexate or D-penicillamine, inhibits the induction of interleukin 1 beta and tumor necrosis factor (TNF) alpha mRNA and protein by either zymosan, lipopolysaccharide (LPS), or various bacteria in mouse macrophages. The auranofin-mediated inhibition of the induction of TNF-alpha mRNA was stronger than that of interleukin (IL) 1 beta mRNA. AF, but not the other drugs, also inhibited zymosan-induced mobilization of arachidonate. The fact that AF inhibited the induction of mRNA for both these proinflammatory cytokines, irrespective of which stimulus was used, may indicate that it affects some common signal transduction step vital to their induction.
Animals↗
Gold(I) Compounds without Significant Aurophilic Intermolecular Interactions: Synthesis, Structure, and Electronic Properties of Ph(3)PAuC(O)NHMe and Au(3)(PhCH(2)N=COMe)(3): Comparative Monomeric and Trimeric Analogues of the Solvoluminescent Trimer, Au(3)(MeN=COMe)(3).
The preparations of Ph(3)PAuC(O)NHMe( )()and Au(3)(PhCH(2)N=COMe)(3) are reported. In solution Ph(3)PAuC(O)NHMe is unstable and readily deposits metallic gold. Colorless needles of the monomeric complex, Ph(3)PAuC(O)NHMe, crystallize in the monoclinic space group P2(1)/c, with a = 8.993(2) Å, b = 22.583(5) Å, c = 8.932(2) Å, beta = 98.22(2) degrees, at 123 K with Z = 4. Refinement of 2609 reflections and 114 parameters yielded R = 0.0455. A hydrogen-bonded intermolecular network links molecular units through N-H.O hydrogen bonds. No aurophilic interactions are present in this solid. The crystal structure of the cyclic trinuclear organogold compound, Au(3)(PhCH(2)N=COMe)(3), reveals that the complex does not associate into a trigonal prismatic array via intermolecular interactions of gold(I) centers as is seen in the triangular complex, Au(3)(MeN=COMe)(3). Rather, the complex packs in a stair-step fashion with eight discrete molecules in the asymmetric unit. Additionally, the solvent-stimulated emission (solvoluminescence) associated with Au(3)(MeN=COMe)(3) is not observed for this complex. Colorless needles of Au(3)(PhCH(2)N=COMe)(3) crystallize in the monoclinic space group P2(1), with a = 17.311(6) Å, b = 34.761(10) Å, c = 18.052(6) Å, beta = 94.73(2) degrees, at 133 K with Z = 16. Refinement of 16 250 reflections and 985 parameters yielded R = 0.0735.
Journal Article↗
Are some major in vivo effects of gold related to microenvironments of decreased selenium?
Gold interacts with selenium in vivo, and the normal distribution of selenium among tissues and subcellular compartments changes. Literature evidence shows that many of the effects of gold compounds on the polymorphonuclear neutrophil, macrophage, and lymphocyte cellular components of the immune system are similar to effects observed in these cellular components in selenium-deficient animals. Affected by these two metals are immune functions related to phagocytic cell migration, phagocytosis, microbial killing, lymphocyte mitogenesis/DNA synthesis, arachidonic acid metabolism/prostaglandin synthesis, and immunoglobulin production. The interaction of gold with selenium in vivo may be responsible for some of the multiparameter-based actions of gold compounds used in the treatment of inflammatory diseases such as rheumatoid arthritis. One mechanism by which gold exerts its clinical effects may be related to its interaction with selenium to produce, in specific microenvironments, decreased levels of this essential trace element.
Animals↗
Synergistic inhibition of T cell proliferation by gold sodium thiomalate and auranofin.
OBJECTIVE: Gold compounds have been employed as therapeutic agents for rheumatoid arthritis (RA) for many years, but the molecular mechanism of their action is unknown. Our studies were undertaken to compare the immunosuppressive activities of parenteral gold (gold sodium thiomalate; GSTM) and orally active gold (auranofin; AF). METHODS: The effects of GSTM and AF on in vitro models of human T cell activation were examined. RESULTS: GSTM and AF were found to exert a synergistic inhibitory effect on human T lymphocyte proliferation in vitro. The concentrations of GSTM and AF that synergistically inhibit T cell proliferation were easily attainable in the serum or synovium of patients treated with these agents. The synergistic inhibitory effect of GSTM and AF was not apparent when interleukin 2 (IL-2)R expression or IL-2 production was examined. The inhibitory effects of GSTM and AF could not be explained by a synergistic effect on proximal signal pathways. CONCLUSION: Our results demonstrate that GSTM and AF exert distinct effects on T cell responsiveness and together synergistically inhibit mitogen induced T cell proliferation. These results suggest the possibility that the combination of GSTM and AF may exert a heightened therapeutic effect in RA compared to the action of either agent alone.
Auranofin↗
Collagenase production by human mononuclear cells in culture: inhibition by gold containing compounds and other antirheumatic agents.
Human peripheral blood mononuclear cells in adherent cultures have been shown to synthesise and secrete collagenase. In the present study we have examined the modulation of collagenase production in these cultures by several antirheumatic agents. Incubation of monocytes in serum free medium with sodium aurothiomalate in concentrations varying from 7.7 X 10(-7) to 7.7 X 10(-3) mol/l resulted in marked dose dependent inhibition of the collagenase production. This inhibition was apparently selective in that total protein synthesis or the viability of the cells were not affected. Similar inhibition of the collagenase production was also noted with auranofin, aurothioglucose, and chloroauric acid. The inhibition with auranofin was achieved with a concentration as low as 7.4 X 10(-8) mol/l. To examine the mechanisms of the inhibition of the collagenase activity induced by sodium aurothiomalate the production of prostaglandin E2 was also measured in the same cell cultures. Sodium aurothiomalate in concentrations greater than 7.7 X 10(-4) mol/l significantly inhibited the prostaglandin E2 production; the prostaglandin E2 production was not inhibited, however, in 7.7 X 10(-5) mol/l concentration, while the collagenase production was reduced by 51.0%. Also, exogenous prostaglandin E2 added to the cultures only slightly reversed the inhibition of the collagenase production by sodium aurothiomalate. Thus the inhibition of collagenase production by sodium aurothiomalate in human adherent mononuclear cell cultures appears to be independent of the inhibition of prostaglandin E2 production. The inhibition of collagenase produced by monocyte-macrophages, as shown here in vitro, may contribute to the clinical efficacy of the compounds tested in the treatment of rheumatoid arthritis.
Anti-Inflammatory Agents↗
Effect of gold on tumor-associated antigens.
A gold compound, which is an anti-rheumatoid agent, was clinically applied to patients showing a high level of tumor-associated antigens. Two patients showed no clear evidence of recurrence except for a high level of tumor-associated antigens. The gold compound was injected i.m. every week at the dose of 25 mg/body for 10 times to a patient showing a high CEA level that had arisen eight years after cervical dissection for a tongue carcinoma. It was also administered every other week for 30 times at the dose of 25 mg/body to a patient showing high CA19-9 and SLX levels five years after palliative left pulmonary resection followed by radiation therapy for left pulmonary carcinoma. The CEA level dropped to the normal limit after 10 injection and remained at that level after cessation of the gold treatment. SLX and CA19-9 levels of the second patient showed lower than initial values, although SLX did not fall to the normal range after the 30 injections. No side effects such as lowering of white blood cell count, BUN elevation, or kidney dysfunction were seen.
Aged↗
The effect of longterm treatment with auranofin and gold sodium thiomalate on immune function in the dog.
Although gold compounds are recognized as effective immunomodulatory agents in the treatment of rheumatoid arthritis (RA), their mechanism of action is controversial. We examined the effect of longterm treatment with 0.6-3.6 mg/kg auranofin (AF) per os q24h, or intramuscular injections of 0.5-2.0 mg/kg gold sodium thiomalate (GSTM) q3d, on 13 variables of immune function in normal dogs. None of the changes in these variables previously attributed to treatment with AF or GSTM could be demonstrated after 6-7 years' dosing. As gold compounds are effective in treating spontaneous RA in dogs, these proposed actions may not be responsible for the remittive effects of chrysotherapy in this disease.
Animals↗
The effects of gold-containing compounds on pregnant rats and their fetuses.
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Abnormalities, Drug-Induced↗
Acute nephropathy induced by gold sodium thiomalate: alterations in renal heme metabolism and morphology.
Gold compounds are used clinically in rheumatoid arthritis therapy. Acute renal toxicity is observed in some patients receiving chrysotherapy. The present study addresses morphofunctional and biochemical changes in rat kidneys during the first 8 days following a single ip injection of gold sodium thiomalate (AuTM), one of the gold compounds presently in clinical use. Compared to controls, AuTM pretreatment resulted in increased urine output and elevated serum creatinine and urea nitrogen concentrations. Also, by Day 8, treated rats had decreased body weights and increased kidney weights. Postmortem examination on Day 1 showed pale and mottled kidneys and diffusely pale inner cortex. Microscopically, there was severe coagulative necrosis of the proximal tubular epithelium. Epithelial regeneration was prominent by Day 4 and was nearly complete by Day 8. The regenerating epithelium was hyperplastic with basophilic cytoplasm and pleomorphic nuclei. Alterations in renal heme biosynthesis and drug metabolism paralleled the morphologic changes. The activity of delta-aminolevulinic acid dehydratase and benzo[a]pyrene hydroxylase were inhibited on Days 1, 2, and 4 following AuTM administration. Decreases in monooxygenase activity were accompanied by decreases in renal cytochrome P-450 levels. In contrast, renal microsomal heme oxygenase activity was elevated 9.5-fold on Day 1 and 2.5-fold on Day 2. By Day 8, all renal enzymatic activities assayed for were similar to those obtained with untreated rats.
Animals↗
Gold-induced immune thrombocytopenia in the dog.
In two seven-year studies with gold compounds in dogs of both sexes, thrombocytopenia was observed after 45 to 72 months of dosing in three of 14 and two of 14 dogs in high-dose groups that received 2.4 to 3.6 mg/kg of auranofin per day orally or 0.5 to 2.0 mg/kg of gold sodium thiomalate intramuscularly once every three days, respectively. An immune basis for the disorder was suggested by the apparent consumptive nature of the thrombocytopenia (increased bone marrow megakaryocytes and large peripheral blood platelets), the response to corticosteroid therapy and the demonstration of increased platelet-associated immunoglobulin. The latter was demonstrated with a solid phase radioimmunoassay and by electron microscopy using a staphylococcal protein A-colloidal gold conjugate. Platelet-associated immunoglobulin decreased as the platelet counts rose, and in one dog monitored over periods of steroid-induced remissions and subsequent relapses, the amount of platelet-associated immunoglobulin G correlated inversely with the platelet count (r = 0.82). These findings suggest that the long-term administration of gold compounds in dogs is associated with a dose-dependent incidence of thrombocytopenia, which is immune-mediated and similar to that associated with parenteral chrysotherapy in man. The application of tests for platelet-associated immunoglobulin to canine patients with immune thrombocytopenia should be useful in the diagnosis of the disorder in clinical practice.
Animals↗
Remittive therapy in rheumatoid arthritis: clinical uses and mechanisms of action.
Evidence has been reviewed supporting the conclusion that gold compounds, anti-malarials and D-penicillamine have the capacity to function as immunosuppressive drugs. Moreover, the results indicate that each has a unique site of action, specifically inhibiting the function of only one of the populations of cells likely to be involved in chronic immunologically-mediated inflammation. Gold compounds and anti-malarials appear to be active by virtue of their capacity to depress the function of mononuclear phagocytes, while D-penicillamine acts by inhibiting a number of the activities of T lymphocytes. These results imply that the means by which these drugs suppress rheumatoid inflammation are fundamentally different. Thus, while each of these compounds acts as a selective immunosuppressive agent, the target cell inhibited appears to be different. The conclusion that the remission-inducing drugs have different modes of action in RA is supported by the clinical observation that the success rate of therapy with one is comparable regardless of antecedent therapy with another (125, 126).
Antimalarials↗
Drug therapy reviews: antirheumatic agents.
The pathophysiology, symptoms and drug treatment of rheumatic disease are reviewed. Antirheumatic drugs reviewed are salicylates (including aspirin, sodium salicylate, choline salicylate, choline magnesium salicylate, salsalate), phenylpropionic acid derivatives (fenoprofen, ibuprofen, naproxen), indole derivatives (sulindac, tolmetin and indomethacin), pyrazolone derivatives (phenylbutazone, oxyphenbutazone), gold compounds, penicillamine, antimalarials mefenamic acid, corticosteroids and immunosuppressives. Simple analgesic therapy (acetaminophen, aspirin, propoxyphene) is used in the early stage of the disease. As the disease progresses, aspirin remains the drug of choice for antiinflammatory activity but the phenylpropionic acid or indole derivatives may be preferred in patients unable to tolerate salicylates. If such nonsteroidal antiinflammatory agents are not effective, parenteral therapy with gold compounds or oral penicillamine usually is indicated. Indomethacin or phenylbutazone, then antimalarials, are resorted to next. Corticosteroids or immunosuppressives are reserved for patients who are unsuccessfully controlled or who have major side effects with the other drugs. Mefenamic acid occupies a very secondary place in rheumatoid arthritis treatment.
Anti-Inflammatory Agents↗
Mucocutaneous side effects and continuation of aurotherapy in patients with rheumatoid arthritis.
AIM: To examine the possibility of the continuation of therapy after achieving clinical improvement in patients with mucocutaneous side-effects of parenteral gold compound therapy (Tauredon, "Byk Gulden", Germany). METHODS AND RESULTS: 40 patients with active seropositive rheumatoid arthritis (average age 42.8 years, average duration of disease 2.8 years) received Tauredon in a dosage of 50 mg/week intramuscularly. 19 patients (47.5%) developed mucocutaneous side effects. Four of them were excluded from the study because of severe skin reactions. In 15 patients with mild or moderate side-effects (local skin rash and stomatitis) aurotherapy was continued after the resolution of adverse reactions. Four out of the 15 patients were withdrawn from the study after restarting the lower dose treatment due to recurrence of dermatitis. 11 out of 19 patients finished 1 year of study with low dose Tauredon. Clinical remission occurred in 4 patients (36.4%) while improvement was registered in 6 patients (54.5%). In one patient (9.1%) no clinical effect was observed. None of these 11 demonstrated any Tauredon toxicity. CONCLUSION: The development of mucocutaneous side-effects should not be considered as an absolute contraindication for the continuation of gold compound therapy. A low dose regimen may allow maintenance of therapeutic effect and improve tolerance in this group of patients. Gold salts, such as disodium aurothiomalate (ATMO have been used in the treatment of rheumatoid arthritis (RA) for over 70 years. They suppress inflammation and retard radiological progression of joint damage [1], but their use is limited by a high incidence of toxic side-effects in about 30% of patients. The commonest side-effect of chrysotherapy is skin toxicity, accounting for up to 60% of all adverse reactions [2]. Rash is most frequent in the first year of therapy, but can occur at any time. Stomatitis occurs in 1-12% of patients and may occur concomitantly with skin rash. The causes of skin rash and stomatitis are still unknown. When mucocutaneous reactions develop, the drug should be withheld until the condition resolves [3]. Approximately 2-3% of patients have to stop treatment because of severe skin rash and mouth ulcers [4]. However we, together with other authors [5, 6, 7, 8, 9] consider that mild to moderate mucocutaneous reactions are not an absolute contraindication for the continuation of gold therapy. The aim of our study is to examine the possibility for the continuation of therapy after achieving clinical improvement in patients with skin rash and stomatitis as a result of treatment with ATM (Tauredon, "Byk Gulden", Germany).
Adult↗
Alterations in intracellular reactive oxygen species generation and redox potential modulate mast cell function.
The administration of mercuric chloride (HgCl2), gold compounds, or D-penicillamine to Brown Norway (BN) rats causes a T helper (Th)2 cell-associated autoimmune syndrome characterized by the production of a number of autoantibodies, marked elevation of serum IgE concentration, and tissue injury in the form of a vasculitis and arthritis. We have recently shown that the same compounds in vitro sensitize BN rat peritoneal mast cells for IgE-triggered mediator release and interleukin-4 mRNA production. We wished to test the hypothesis that these agents influence mast cell function via an effect on intracellular reactive oxygen species (ROS) production/redox balance. Mast cells were obtained from BN rats by peritoneal washout. Incubation with HgCl2, gold compounds or D-penicillamine (the latter only in the presence of copper ions) led to the intracellular production of ROS as shown by the oxidative production of the fluorescent compound 2',7'-dichlorofluorescein. Mast cells were more sensitive than splenocytes to this effect. Direct oxidative stress (exposure to H2O2) produced a similar sensitization for mediator release to that caused by HgCl2. Inhibition of ROS formation by desferrioxamine or catalase diminished the enhancement of IgE-mediated serotonin release caused by HgCl2, as did replenishment of intracellular glutathione. 2-Mercaptoethanol exacerbated the toxicity of HgCl2, perhaps due to the formation of a lipophilic complex that enhanced HgCl2 uptake. Blocking of glutathione synthesis increased the toxicity of HgCl2, but also abolished any sensitizing effect on mediator release. These results support three main predictions of our hypothesis: (1) the compounds known to influence mast cell function all lead to the generation of ROS within the mast cell; (2) direct oxidative stress causes sensitization for mediator release by the mast cell; and (3) modulation of ROS production/redox balance within the mast cell modulates the effects of these compounds on mast cell function. The balance of oxidative/antioxidative influences may play an important role in the modulation of mast cell function, particularly in the context of chemically induced autoimmunity.
Animals↗
The cellular and molecular pharmacology of auranofin and related gold complexes.
Investigations of the molecular pharmacology of auranofin (AF) and related gold compounds reveal that these gold complexes interact with proteins primarily via sulfhydryl reactions. Moreover, cell association, distribution and efflux of auranofin and related gold complexes can be explained by sequential sulfhydryl exchanges. The rate of the reactions and potential interactions with sulfhydryl groups in different environments vary according to the ligands associated with the gold. Secondary interactions of AF, such as the formation of triethylphosphine oxide and products of lipid oxidation, may also depend upon characteristics of the ligands. The mechanisms of cytotoxicity by which auranofin and closely related compounds affect cells probably include interactions with key membrane structural proteins, protein crosslinks, and effects on key membrane localized enzymes, e.g., phospholipase C. Other cellular effects may include inhibition of DNA polymerase and other enzymatic processes. Resistance to auranofin is mediated by induction of metallothionein in the cells studied. Gold-loaded metallothionein is less stable to proteolysis than cadmium-bound metallothionein, which probably explains the relatively ephemeral nature of resistance to auranofin.
Animals↗
Remission-inducing therapy in rheumatoid arthritis.
Rheumatoid arthritis is characterized by immunologically mediated chronic inflammation of synovial structures. Remission-inducing drugs, such as gold compounds, antimalarials, and D-penicillamine, have been shown to suppress disease activity in rheumatoid arthritis while having minimal nonspecific anti-inflammatory properties. The possibility that these agents are effective because they modulate the underlying immunologic reactivity prompted an examination of the immunosuppressive properties of these drugs. The evidence indicates that immunosuppression is an action that is shared by these agents and thus supports the view that remission induction may result from suppression of the immunologic activity that underlies rheumatoid inflammation. Despite the fact that these agents can function as immunosuppressives, each appears to have a unique site of action, specifically inhibiting the function of only one of the populations of cells likely to be involved in chronic immunologically mediated inflammation. Gold compounds and anti-malarials appear to be active by virtue of their capacity to depress various functions of mononuclear phagocytes, while D-penicillamine acts by inhibiting a number of the activities of T lymphocytes. These results imply that the means by which these drugs suppress rheumatoid inflammation are fundamentally different. This suggests the conclusion that the remission-inducing drugs may be classified as T cell-active and mononuclear phagocyte-active agents. A better understanding of the pathophysiology of rheumatoid arthritis should thus be helpful in deciding which of these classes of drugs is appropriate in individual cases.
Anti-Inflammatory Agents↗