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At least 19 recordsLinked to original sources
PubMed1979

Gold and thiol compounds in the treatment of rheumatoid arthritis: excretory fate and tissue distribution of thiomalate in relation to gold after administration of myocrisin (auro-thiomalate).

Double isotope-labelled auro thiomalate (Au195-C14-thiomalate) has been administered to mice and rats, and the excretory fate and tissue distribution have been studied. The results show that the gold and the thiomalate separate in vivo resulting in protein-bound gold and release of free thiomalate. About half of this thiol is excreted in the urine during the first day and the remaining half is taken up by the tissues. Thiomalate penetrates cellular membranes poorly, but is able to interact slowly with proteins (mixed disulphide formation). Part of the thiomalate which remains in the body is membrane bound. In contrast to penicillamine little thiomalate remains in circulation a few hours after administration. Gas chromatography--mass spectrometry has been used to search for the presence of free thiomalate in rheumatoid arthritis patients on Myocrisin (auro thiomalate) therapy. Thiomalate was found in their urine, but not in serum and synovial fluid 20 hours after administration. As thiomalate is released in the body after administration of Myocrisin. the question arises whether this thiol, like penicillamine, may have a beneficial effect in the treatment of rheumatoid arthritis.

Animals↗
PubMedDate not supplied

[Reactions against sodium-auro-thiomalate in the treatment of rheumatoid arthritis].

The authors report the case of a 58 year old female patient with rheumatoid arthritis. About 4 hours after each intramuscular injection of Myochrysin (Sodium-auro-thiomalate 5%) she showed undesired reactions such as sialorrhea, nausea, vomiting, abdominal pain, diarrhea, apathy, weakness, head ache, breast swelling, perspiration, feeling of incident death. The following day these symptoms declined, the joint pain, however, increased. The reaction recurred with each of the 5 Sodium-auro-thiomalate injections, but not after injections of 5% Solganal (Aurothioglucose). It is supposed that these side effects are connected with the quick absorption of the Sodium-auro-thiomalate in aqueous solution. The Aurothioglucose in oil suspension would not cause such reactions after an intramuscular injection because of its slower absorption.

Arthritis, Rheumatoid↗
PubMed1977

99mTc-thiomalic acid complex: a nonstannous chelate for renal scanning.

Thiomalic acid (monomercaptosuccinic acid) has been labeled with 99mTc without the use of an intermediary reducing agent. Tissue distribution studies in rats following the injection of 99mTc-tagged thiomalic acid (99mTc-TMA) showed 40-48% of the injected dose in the kidneys. Renal incorporation of this compound was influenced by various parameters such a pH, quantity of thiomalic acid, heating time, and the preparation-injection interval. Scintigrams of a midline kidney slice showed that the 99mTc activity concentrated mainly in the renal cortex. As a proposed renal-imaging agent 99mTc-TMA compared favorably with 99mTc-Sn-dimercaptosuccinate and 99mTc-penicillamine regarding the precent incorporation into the kidney and was superior in this respect to 99mTc-Sn-glucoheptonate and 99mTc-Sn-diethylenetriamine pentaacetic acid. The 99mTc-TMA was also shown to be highly stable through 24 hr. The reagent can be made available in kit form and is easily combined with 99mTc in two steps. Finally, the absence of stannous ion in the 99mTc-TMA complex should avoid the problem of interference with other procedures involving pertechnetate 99mTco4- as the imaging agent.

Animals↗
PubMed1975

Investigations on the influence of cyclophosphamide, gold sodium thiomalate and D-penicillamine on nystatin oedema and adjuvant arthritis.

Cyclophosphamide (5 or 10 mg/kg p.o.) and Gold sodium thiomalate (0 or 40 mg/kg i.m.) inhibit after repeated administrations (5 days) all the phases of Nystatin edema, whereas a single administration is ineffective. D-Penicillamine (25 or 100 mg/kg p.9.) inhibits the early phases of Nystatin edema after a single administration whereas repeated administrations are almost ineffective. An early treatment with Cyclophosphamide (2.5 mg/kg p.o.) simply delays the appearance of the secondary lesions of adjuvant arthritis but inhibit the development of the primary lesions. A late treatment with Cyclophosphamide as both the types of treatment with Gold sodium thiomalate (10 mg/kg i.m.) are effective against primary and secondary lesions. The only effect of D-Penicillamine (50 mg/kg p.o.) in adjuvant arthritis is a significant increase of the intensity of secondary lesions during the late treatment. It is suggested that the anti-inflammatory activity of Cyclophosphamide does not depend exclusively upon its immunosuppressant activity and that D-Penicillamine is effective on some cell population committed in the inflammatory reactions.

Animals↗
PubMed1979

Alterations in human monocyte structure and function induced by incubation with gold sodium thiomalate.

The effect of in vitro indubation with gold sodium thiomalate (GST) on the morphology and functional activity of human mononuclear phagocytes (Mphi) was examined. Human peripheral blood Mphi that had been incubated with GST (25 micrograms/ml) for 4 days developed large intracytoplasmic vacuoles. Similar vacuolization developed after incubation with gold chloride but not with thiomalic acid. GST pre-incubation also induced a number of functional alterations in Mphi. GST incubation had little effect on glass adherence or FC receptor-mediated particle binding but markedly diminished pinocytosis of horseradish peroxidase and phagocytosis of IgG opsonized erythrocytes. These data indicate that the action of GST in rheumatoid arthritis may result from its capacity to alter the functional capability of Mphi.

Cell Survival↗
PubMed1977

Acute myocardial infarction following gold sodium thiomalate induced vasomotor (nitritoid) reaction.

A vasomotor (nitritoid) reaction occurred following an initial injection of gold sodium thiomalate (GST; Myochrysine) in a 69-year-old man with rheumatoid arthritis (RA). An acute anterior wall myocardial infarction, documented by serial electrocardiographic and serum enzyme changes, developed immediately thereafter. A second patient, a 49-year-old man with RA and a history of GST-associated vasomotor reactions, was monitored clinically and electrocardiographically after GST administration. Sinus tachycardia developed and peripheral blood pressure fell within 2 minutes of injection, simultaneous with the onset of vasomotor symptoms. Vasomotor reactions from GST may compromise myocardial perfusion by their action on arteriolar smooth muscle, and thus result in peripheral vasodilatation, or they may act by adrenergic discharge initiated by such a reaction, and thus increase myocardial work and oxygen demand. Aurothioglucose (Solganal), rarely produces vasomotor reactions, and may be preferred to GST in elderly RA patients with concomitant cardiovascular disease or atherosclerosis.

Aged↗
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↗
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↗
PubMed1992

Characterization of gold in urine and bile following administration of gold sodium thiomalate with chelating agents to rats.

Gold was characterized in the urine and bile of rats treated with D-penicillamine (D-PEN), 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercaptopropane sulphonate (DMPS), or N-(2-mercapto-2-methylpropanoyl)-L-cysteine (bucillamine) immediately after gold sodium thiomalate (AuTM) injection by both gel chromatographic and electrophoretic methods. It is suggested that the gold in the urine and bile after AuTM administration was predominantly bound to high molecular weight compounds. The characterization of gold in the urine after administration of AuTM with D-PEN, DMSA, or DMPS showed that most of the gold was bound to the chelating agents. In the treatment with the chelating agents such as D-PEN and DMPS, the gold was mainly excreted as a gold-chelating agent compound in the bile and a minor portion of the gold was present in the form of a gold-L-cysteine compound and high molecular weight compounds. DMSA treatment showed that a major portion of the gold was bound to high molecular weight compounds in the bile and a minor portion of the gold was present in the forms of gold-DMSA and gold-L-cysteine compounds. The administration of AuTM and bucillamine indicated that the gold was mainly present as a gold-Me-bucillamine compound in the urine and a gold-bucillamine compound in the bile.

Animals↗
PubMed1979

Effect of gold sodium thiomalate on murine lymphocyte functions.

The in vitro effects of gold sodium thiomalate (GTM) on various murine splenic lymphocytic functions were tested. The presence of GTM in cultures of splenic cells suppressed anti-hapten responses to both thymus-independent and thymus-dependent antigens. GTM also suppressed the in vitro generation of cytotoxic effector cells as well as the mitogenic response to both T cell and B cell mitogens. This suppression could not be reversed by the addition of irradiated spleen cells. Spleen cells exposed to GTM for 4 hr prior to culture also exhibited similarly suppressed functions, although their functional capacity could be fully restored by the addition of irradiated spleen cells. These results show that GTM inhibits both humoral and cellular immune mechanisms and appears to act primarily at the accessory (macrophage) cell level, with perhaps a secondary effect on T lymphocytes.

Animals↗
PubMed1979

Immunopharmacology of auranofin and gold sodium thiomalate: effects on humoral immunity.

The effect of auranofin and gold sodium thiomalate (GST) on antibody production was evaluted using antibody-dependent cellular cytotoxicity and complement-dependent antibody responses to sheep red blood cells (SRBC) and L929 fibroblasts. The results indicated that auranofin was capable of depressing antibody production to L929 cells, but inconsistently depressed the response to SRBC in the mouse. GST, however, stimulated both responses. In vitro, both compounds inhibit secretion of antibody. These results demonstrate that auranofin, in contrast to GST, is capable of suppressing humoral immunity which may explain its more rapid effect on immunological parameters in RA.

Animals↗
PubMed1979

Effect of gold sodium thiomalate on fibrinolysis.

Effects of gold sodium thiomalate (GST) on fibrinolytic activities of normal blood and plasma, polymorphonuclear leukocytes (PMN), purified PMN fibrinolytic enzymes, and the enzyme, plasmin, were examined by 125I-fibrin radiometric assay. Of the 2 enzymes accounting for all of the fibrinolytic activity extractable from PMN, the chymotrypsin-like enzyme (cathepsin G),but not the elastase, was inhibited by GST (50% inhibition at 10-6M, 80% inhibition at 10-5M). Plasmin was not inhibited by GST (10-4M to 10-7 M), and these concentrations had no effect on fibrinolytic activities of normal blood and plasma (6 subjects). Activities of PMN preparations from only 2 of 5 normal subjects were inhibited by GST (maximum inhibition of 29% at 10-5 M). These findings indicate a differential effect of GST on PMN elastase and cathepsin G, and suggest a minor role for the latter in normal PMN fibrinolytic activity.

Cathepsins↗
PubMed1992

Immunomodulatory effects of therapeutic gold compounds. Gold sodium thiomalate inhibits the activity of T cell protein kinase C.

Previous studies have shown that the gold compounds, gold sodium thiomalate (GST) and auranofin (AUR), which are effective in the treatment of rheumatoid arthritis, inhibit functional activities of a variety of cells, but the biochemical basis of their effect is unknown. In the current studies, human T cell proliferation and interleukin 2 production by Jurkat cells were inhibited by GST or AUR at pharmacologically relevant concentrations. Because it has been documented that protein kinase C (PKC) is involved in T cell activation, the capacity of gold compounds to inhibit PKC partially purified from Jurkat cells was assayed in vitro. GST was found to inhibit PKC in a dose-dependent manner, but AUR caused no significant inhibition of PKC at pharmacologically relevant concentrations. The inhibitory effect of GST on PKC was abolished by 2-mercaptoethanol. To investigate the effect of GST on the regulation of PKC in vivo, the levels of PKC activity in Jurkat cells were examined. Cytosolic PKC activity decreased slowly in a concentration- and time-dependent manner as a result of incubation of Jurkat cells with GST. To ascertain whether GST inhibited PKC translocation and down-regulation, PKC activities associated with the membrane and cystosolic fractions were evaluated after phorbol myristate acetate (PMA) stimulation of GST incubated Jurkat cells. Translocation of PKC was markedly inhibited by pretreatment of Jurkat cells with GST for 3 d, but the capacity of PMA to down-regulate PKC activity in Jurkat cells was not altered by GST preincubation. The functional impact of GST-mediated downregulation of PKC in Jurkat cells was examined by analyzing PMA-stimulated phosphorylation of CD3. Although GST preincubated Jurkat cells exhibited an increased density of CD3, PMA-stimulated phosphorylation of the gamma chain of CD3 was markedly inhibited. Specificity for the inhibitory effect of GST on PKC was suggested by the finding that GST did not alter the mitogen-induced increases in inositol trisphosphate levels in Jurkat cells. Finally, the mechanism of the GST-induced inhibition of PKC was examined in detail, using purified PKC subspecies from rat brain. GST inhibited type II PKC more effectively than type III PKC, and also inhibited the enzymatic activity of the isolated catalytic fragment of PKC. The inhibitory effect of GST on PKC activity could not be explained by competition with phospholipid or nonspecific interference with the substrate. These data suggest that the immunomodulatory effects of GST may result from its capacity to inhibit PKC activity.

Auranofin↗