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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↗
PubMed1994

Effect of gold sodium thiomalate and its thiomalate component on the in vitro expression of endothelial cell adhesion molecules.

Endothelial adhesion molecules play an important role in the tissue recruitment of leukocytes in inflammatory conditions such as rheumatoid arthritis. We have investigated the effect of the antirheumatic drug gold sodium thiomalate on adhesion molecule protein and mRNA expression in cultured human endothelial cells. Gold sodium thiomalate inhibited cytokine (TNF, IL-1, IL-4)-stimulated expression of vascular cell adhesion molecule-1 and E-selectin but not intercellular adhesion molecule-1 on endothelial cells. Gold sodium thiomalate also suppressed TNF-stimulated increases in vascular cell adhesion molecule-1 and E-selectin mRNA levels but had no effect on intercellular adhesion molecule-1 mRNA. Thiomalate (mercaptosuccinate), but not gold thioglucose or D-penicillamine, mimics the effect of gold sodium thiomalate at equimolar concentrations. We propose that the inhibition of vascular cell adhesion molecule-1 and E-selectin expression by gold sodium thiomalate is due to its thiomalate and not its gold component. Gold sodium thiomalate has a direct effect on endothelial adhesion molecule expression, and this may contribute to its antiinflammatory activity.

Animals↗
PubMed1990

The effect of gold sodium thiomalate and its constituent part, thiomalate, on the virus titres and the lysosomal enzyme activity in peritoneal macrophages of Swiss/A2G mice infected with the avirulent strain of Semliki Forest virus.

Treatment of adult mice with gold sodium thiomalate made the normally non-lethal Semliki Forest virus infection lethal. Associated with this was a significant increase in brain virus titre and a depression of peritoneal macrophage lysosomal enzyme activity. In contrast, treatment of adult mice with the constituent part, thiomalate, did not make the non-lethal Semliki Forest virus infection lethal. Brain virus titre and peritoneal macrophage lysosomal enzyme activity were comparable to the controls. The mechanism by which gold sodium thiomalate increases the virulence of Semliki Forest virus is discussed.

Acid Phosphatase↗
PubMed1990

Gold sodium thiomalate (GTM) induces hypersensitivity to thiomalate, the thiol carrier of GTM.

A case of the gold sodium thiomalate (GTM)-induced eruptions with thiomalate (TM) hypersensitivity was reported. A 61-year-old Japanese woman developed lichenoid and seborrheic dermatitis (SD)-like eruptions with alopetia, when the total dosage of GTM administered for rheumatoid arthritis became 110 mg. The eruptions slowly disappeared with pigmentation after discontinuance of the GTM therapy, and the resumption resulted in the development of similar eruptions. She showed a positive reaction to GTM in an intradermal test. She also showed a positive response to TM, which is the thiol carrier of GTM, in the patch test, but a negative one to metallic gold. After administration of auranofin (AF), she also developed the SD-like eruptions with hypersensitivity to metallic gold as well as AF on patch testing, but did not develop the lichenoid ones. Our animal experiments revealed an almost complete cross reaction between GTM and TM, but only a partial one between GTM and aurothioglucose, which have dissmilar structures in the carrier part for gold. Probable roles of hypersensitivity to TM and metallic gold, which are metabolites of GTM, were discussed, respectively, in the genesis of the GTM-induced lichenoid eruptions and the AF-induced SD-like eruptions.

Animals↗
PubMed1991

Action of gold sodium thiomalate on experimental thrombosis in vivo.

In order to study the effect of gold compounds on the action of thrombin in vivo, experiments were performed to measure platelet survival and the weight of thrombus formation in experimental models of intra-aortic thrombosis by two indwelling aortic catheter methods. We have called these the long and short catheter methods. Platelet survival was reduced in all gold-treated and control animals which had indwelling aortic catheters. In the long catheter model, New Zealand White male rabbits were treated with one of the following: gold sodium thiomalate, sterile water, gold thioglucose, gold sodium thiosulfate, disodium thiomalate. Gold sodium thiomalate-treated rabbits had a reduced weight of experimentally induced intra-aortic thrombi compared with animals treated with sterile water or equimolar concentrations of gold thioglucose, gold sodium thiosulfate, or disodium thiomalate. This reduction in thrombus weight in the animals treated with gold sodium thiomalate was not reflected by changes in platelet survival or fibrinolysis. The serum gold levels achieved in these in vivo experiments was in the range of 5.0 X 10(-5) to 1.0 X 10(-4) M. These values are comparable to levels which can be achieved in human subjects immediately after a gold injection. In the short catheter model, New Zealand White male rabbits were treated with either gold sodium thiomalate, gold thioglucose, disodium thiomalate, or auranofin. Controls were given either water or 0.05% chlorocresol. Water-treated and gold sodium thiomalate-treated animals were also given 51Cr-labeled platelets and 125I-fibrinogen before insertion of the catheter.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Site of action for the inhibition by gold sodium thiomalate of rabbit platelet activation.

The inhibitory action of the gold-based drug gold sodium thiomalate was investigated in rabbit platelets. Gold sodium thiomalate at concentrations of 0.25-13 x 10(-4) M inhibits collagen-, ADP-, and 9,11,dideoxy-11 alpha,9 alpha-epoxymethanoprostaglandin F2 alpha (U46619)-induced aggregation as well as collagen- and U46619-induced serotonin release. This inhibition occurs in both Tyrodes-albumin or Tyrodes-gelatin buffer systems. Preincubation of gold sodium thiomalate with platelets resulted in less inhibition as the time of preincubation increased. The inhibitory effect of gold sodium thiomalate could be removed by washing the platelets. Other sulfhydryl-reacting compounds, such as D-penicillamine, thiomalic acid, 5,5'-dithiobis-2-nitrobenzoic acid, and 6,6'-dithiodinicotinic acid, were all capable of inhibiting collagen-induced aggregation and serotonin release. Evidence is presented that gold sodium thiomalate interferes with the activation of rabbit platelets by several activators, that this action of gold sodium thiomalate is similar to the action of other sulfhydryl-reacting agents, that this inhibition is likely occurring at the membrane, and that the action of the drug is not dependent on the presence of albumin.

Animals↗
PubMed1980

Fate of the gold and the thiomalate part after intramuscular administration of aurothiomalate to mice.

Double isotope-labelled aurothiomalate (195Au-14C-thiomalate) has been administered to mice, 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 bound to tissue membranes and cells. Although thiomalate penetrates cellular membranes slowly in vitro. the compound is found in all organs, mostly in the liver and the kidneys, after administration of aurothiomalate. Separation of the gold moiety from its thiol carrier also takes place in man. This explains the finding of free thiomalate in the urine of patients receiving aurothiomalate intramuscularly. As thiomalate has now been shown to possess penicillamine-like biological activities it is suggested that at least part of the antirheumatic effects of aurothiomalate may be due to the thiol carrier being released in the body.

Animals↗
PubMed1989

[A study on the inhibition of non-specific neutral proteinase by gold salt. Part 1. Gold sodium thiomalate].

The inhibitory effect of gold sodium thiomalate on non-specific neutral proteinase (EC 3.4.24.4) was investigated in vitro, in order to clarify the suppressive mechanism of the inflammatory process of joints by gold salt. The neutral proteinase was inhibited time- and concentration-dependently by gold salt. When the enzyme was incubated with 1 x 10(-2)M gold sodium thiomalate for 60 minutes, almost 100% of the activity was lost. Even at a lower concentration (1 x 10(-5)M, gold sodium thiomalate inhibited the enzyme time-dependently after longer incubation (3 or 9 hours). However, the same concentration of gold sodium thiomalate previously incubated with alpha-casein did not inhibit it. The results obtained here suggest that gold sodium thiomalate may inhibit the enzyme by binding it. The delay of neutral proteinase inhibition by gold sodium thiomalate seemed to be dependent on the concentration of gold salt.

Antirheumatic Agents↗
PubMed1984

Circulating thiomalate after administration of disodium aurothiomalate: impurity or active metabolite?

During studies of the metabolism of disodium aurothiomalate in patients with rheumatoid arthritis we have found that its pharmaceutical preparation. Myocrisin, contains 4 to 8% of free thiomalate. To establish whether the free thiomalate previously reported in plasma and urine of patients receiving Myocrisin is a true metabolite or results from this impurity, we prepared aurothiomalate containing 0.1% thiomalate. Intramuscular injection of the purified drug to 2 healthy subjects produced easily detectable levels of thiomalate in both plasma and urine; 7.7 and 9.8% respectively of the doses given were recovered in urine as free thomalate within 4 h. Thus, dissociation of disodium aurothiomalate does occur in vivo, releasing both gold and free thiomalate as potentially active forms.

Chemical Phenomena↗
PubMed1988

Inhibition of production of macrophage-derived angiogenic activity by the anti-rheumatic agents gold sodium thiomalate and auranofin.

We have investigated the effect of gold sodium thiomalate and auranofin, gold compounds employed in the treatment of rheumatoid arthritis, on production of macrophage-derived angiogenic activity. Elicited mouse peritoneal macrophages were cultured in the presence or absence of gold compounds or thiomalic acid, and the macrophages or their conditioned media were then assayed for their angiogenic activity in rat corneas. Control macrophage conditioned medium was potently angiogenic. In contrast, conditioned medium from gold or thiomalic acid treated macrophages was not. Addition of gold compounds or thiomalic acid to control macrophage conditioned medium did not inhibit its angiogenic activity. Drug treatments did not significantly affect macrophage lactate dehydrogenase release, lysozyme release, or protein synthesis. We conclude that gold sodium thiomalate and auranofin potently reduce the detectable angiogenic activity produced by macrophages.

Animals↗
PubMedDate not supplied

Inhibitory effects of gold sodium thiomalate on DNA polymerase alpha.

The usefulness of gold compounds in the therapy of rheumatoid arthritis is well established, however, the pharmacological mechanisms of the compounds are still unclear. In this report, effects of gold compounds on DNA synthesis were examined. Gold sodium thiomalate inhibited DNA synthesis in the HeLa "nuclei system" as well as in the enzyme reaction using DNA polymerase alpha. More precisely, gold sodium thiomalate inhibited the activity of DNA polymerase alpha using activated DNA, poly[d(A-T)] or poly[d(G-C)] for the template, but did not inhibit the activity of DNA polymerase I with each template. The compound had also no inhibitory effect on DNA polymerase beta or gamma. On the other hand, auranofin inhibited the incorporation of [3H]thymidine into HeLa DNA but did not inhibit DNA synthesis in the HeLa "nuclei system". The inhibition of DNA polymerase alpha activity by gold sodium thiomalate was competitive with poly(dA).oligo(dT) for template but noncompetitive with dTTP. Thus, gold sodium thiomalate is a potent and specific inhibitor of DNA polymerase alpha and this inhibitory effect could play an important role in the therapeutic and pharmacological effects of gold sodium thiomalate.

Auranofin↗
PubMed1982

Fate of the thiomalate part after intramuscular administration of aurothiomalate in rheumatoid arthritis.

The excretory fate and plasma level of thiomalate were studied after intramuscular administration of auro-14C-thiomalate to 3 patients with rheumatoid arthritis. The gold and the thiomalate parts separated in vivo, and the free thiomalate was excreted in the urine, rapidly at first and then slowly. After one day about 60% of the 14C-label had been recovered in the urine. The plasma level also declined rapidly. The results are in complete agreement with those previously described in animal experiments.

Adult↗
PubMed1983

Comparison of auranofin, gold sodium thiomalate, and placebo in the treatment of rheumatoid arthritis. Subsets of responses.

A comparison of placebo, auranofin, and parenteral gold sodium thiomalate therapy in 209 patients with active rheumatoid arthritis was performed in a 21-week prospective, controlled, double-blind multicenter trial. When the 161 patients who completed at least 20 weeks of treatment were analyzed for different degrees of response, no remissions were identified. When 50 percent or greater improvement of pain/tenderness scores were compared for end of trial versus entry values, 9 percent of placebo-treated patients, 34 percent of auranofin-treated patients, and 48 percent of gold sodium thiomalate-treated patients showed important improvement that was statistically significant for both gold treatments. When 50 percent improvement for joint swelling was analyzed, 12 percent of the placebo-treated group, 28 percent in the auranofin-treated group, and 37 percent in the gold sodium thiomalate-treated group showed this degree of improvement. Auranofin almost achieved statistical significance for improvement in joint swelling when compared with placebo (p = 0.07), but gold sodium thiomalate was much better than placebo (p = 0.009). There was no statistically significant difference between the two gold treatments. Thus it appears that a subset of patients had an important response to gold therapy that would not be evident by the usual analyses of mean or median changes. Analysis for predictors of response did not discriminate between responders and nonresponders. Because the trial was limited to 21 weeks of therapy, no prediction of the longer-term-effects, especially for auranofin, should be inferred.

Adolescent↗
PubMed1995

Skin testing with gold sodium thiomalate and gold sodium thiosulfate.

Recently gold sodium thiosulfate was found to be the most common sensitizer after nickel sulfate in our routinely patch tested dermatitis patients. When patients hypertensive to gold sodium thiosulfate were tested with another monovalent gold salt, gold sodium thiomalate, at equimolar concentrations, in principle, no positive reactions were obtained. Gold sodium thiomalate is used for treatment of rheumatoid arthritis, a treatment with a high frequency of adverse skin reactions. To investigate whether the reactivity difference between the 2 gold salts was due to differences in bioavailability, some experiments were carried out. Intracutaneous tests with the 2 gold salts at equimolar concentrations yielded equivalent reactions. When the concentration of gold sodium thiomalate for epicutaneous testing was increased, all 12 gold-allergic patients reacted positively. Therefore, in our department, contact allergy to gold sodium thiomalate is probably as common as contact allergy to gold sodium thiosulfate.

Administration, Cutaneous↗
PubMed1984

Free thiomalate in plasma and urine of patients receiving sodium aurothiomalate.

Free thiomalate is measureable in the plasma and urine of patients with rheumatoid arthritis receiving sodium aurothiomalate (Myocrisin). Plasma concentrations and urinary excretion of free thiomalate were measured in 8 patients by high-performance liquid chromatography and electrochemical detection. After an initial intramuscular dose of 20 mg sodium aurothiomalate, free thiomalate was detected in plasma within 15 min, peak levels of up to 600 nmol/l occurring at 30 min. Plasma levels declined rapidly thereafter. During the first 24 h between 2 and 16% of the injected dose of aurothiomalate was recovered in the urine as free thiomalate, maximum excretion occurring during the first hour.

Adult↗
PubMed1993

Preparation of a gelatin-binding conjugate containing gold thiomalate.

Plasma fibronectin has a range of binding sites, for ligands, including denaturated collagen (gelatin). It has been proposed that this activity may be used for nonimmune drug targeting to sites in the extra-cellular matrix such as the targeting of gold thiomalate to rheumatoid joints. In the present study, a novel conjugate has been developed, consisting of the gold thiomalate bound at high density to the gelatin-binding domain of fibronectin, through a polylysine carrier. Isolation and cross-linking of suitable fragments of fibronectin (relative molecular weights 65 and 52 kDa) to polylysine is followed by conjugation to gold thiomalate on a solid phase, gelatin-agarose affinity absorbent. Although gold thiomalate has the ability to inactivate, the protein-gold conjugate produced by this technique retained its gelatin-binding activity.

Drug Carriers↗