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PubMed1988

Biological action of colorless and yellow solutions of gold sodium thiomalate on thrombin activity and the mixed lymphocyte reaction.

Gold sodium thiomalate is a pale yellow powder which forms a colorless solution when added to sterile water. The marketed form of gold sodium thiomalate is a pale yellow solution. The yellow color develops as a result of the sterilization process. This study demonstrates that the physical change induced in the drug by the sterilization process has no effect on the action of gold sodium thiomalate on the serine esterase thrombin, nor on the inhibition of the mixed lymphocyte response. Thus it is unlikely that the yellow component is responsible for benefit in rheumatoid arthritis. If the components creating the yellow color cause toxicity, the preparation and/or formulation of the drug should be changed.

Blood Platelets↗
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↗
PubMed1986

Effect of sodium thiomalate on immune complex-induced release of lysosomal enzymes from human polymorphonuclear leucocytes.

The extracellular release of beta-glucuronidase and beta-N-acetylglucosaminidase from normal human polymorphonuclear leucocytes initiated with bovine serum albumin/anti-bovine serum albumin immune complex (15 micrograms/ml) was significantly inhibited (p less than 0.01) by pretreatment with increasing concentrations (10(-8) M, 10(-7) M, 10(-6) M and 10(-5) M) of sodium thiomalate in a time- and dose-related fashion. Also, beta-glucuronidase and beta-N-acetylglucosaminidase exhibited similar responses to the effects of bovine serum albumin/anti-bovine serum albumin or sodium thiomalate. In contrast, neither bovine serum albumin/anti-bovine serum albumin nor sodium thiomalate provoked appreciable leakage of the cytoplasmic enzyme, lactate dehydrogenase. This indicates that cell integrity remains intact under the experimental conditions described.

Acetylglucosaminidase↗
PubMed1988

Failure of oral thiomalate to act as an alternative to intramuscular gold in rheumatoid arthritis.

Ten patients with active rheumatoid arthritis (RA) were entered into a pilot study to evaluate the effectiveness of thiomalic acid as a disease modifying agent and to assess its toxicity. Oral thiomalic acid (100 mg) was given daily for up to six months. Changes in disease activity were recorded monthly and all side effects noted. No patient recorded any improvement in subjective well being, pain score, or duration of early morning stiffness. No significant change occurred in articular index or haemoglobin (Hb); the erythrocyte sedimentation rate (ESR) showed a tendency to increase. Only three patients completed six months' treatment; six withdrew because of toxic reactions (three with rashes and three with severe gastrointestinal upset) and one because of lack of effect. Thiomalic acid alone appears to have no significant antirheumatic activity and is associated with an unacceptably high incidence of adverse reactions.

Absorption↗
PubMed1989

Gold sodium thiomalate toxicity in cadmium-sensitive and cadmium-resistant Chinese hamster ovary cells.

Gold sodium thiomalate was incubated with one cadmium-sensitive cell line and two cadmium-resistant variants. The resistant lines have been reported to synthesize metallothionein (MT) in response to both cadmium and zinc, whereas the sensitive line does not. All cell lines showed a dose-dependent inhibition of growth as a result of gold sodium thiomalate treatment. However, daily comparisons of cell numbers indicate that the cadmium-resistant lines actually increase in number at the highest gold concentrations, whereas numbers of cells in the nonresistant line decrease. MT biosynthesis was measured by monitoring the incorporation of [35S )cysteine into low molecular weight protein. None of the cells synthesized MT in response to gold. When incubated with both zinc and gold, MT was synthesized by both of the cadmium resistant lines; however, the amount of MT synthesized was reduced in the presence of gold which appears to inhibit the uptake of [35S]cysteine by all the cell lines. Although MT is synthesized in the presence of zinc and gold sodium thiomalate, the MT does not have a significant effect on the ability of these cells to withstand high concentrations of gold.

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↗
PubMedDate not supplied

Inhibition of complement by gold sodium thiomalate.

The effect of gold sodium thiomalate on C3 and factor B activation by monosodium urate monohydrate (MSUM) and zymosan was studied using a quantitative immunoelectrophoretic assay for complement activation. C3 and factor B conversion by the classical pathway activator MSUM, was inhibited 50% and 100% by 3.2 x 10(-4)M and 10(-3)M gold sodium thiomalate, respectively. C3 and factor B conversion by the alternative pathway activator, zymosan, was much less susceptible to inhibition by gold. Gold at 10(-3)M, inhibited alternative pathway activation by only 30%. A 50% inhibition would have required 10(-2)M gold. There was no significant inhibition of complement activation through either pathway by less than 10(-4)M gold. Sodium thiomalate alone showed no inhibition. Studies using other crystals and immune complexes were confirmatory. Thus, there was no appreciable inhibition of the complement system at concentrations of gold attainable in the serum of patients receiving chrysotherapy. The in vivo significance of these findings is unknown.

Complement C3↗
PubMed1982

Pharmacokinetics of gold sodium thiomalate.

Two normal males participated in a study designed to examine the disposition of gold given intravenously and intramuscularly as gold sodium thiomalate. Blood samples were collected for 30 days, urine and feces for ten. A triphasic decay pattern in plasma gold concentrations was observed. Terminal log-linear phases corresponded to a mean disposition half-life of 12.5 days. Absolute bioavailability of IM gold sodium thiomalate appears to be variable with one subject having complete absorption and the other absorbing 64% of the administered IM dose. The major route of elimination of an IV dose of gold sodium thiomalate is urinary excretion, with a mean of 35% of the dose found in the urine in ten days. Fecal elimination accounts for an additional 9.4% of the IV dose excreted in ten days, probably as a result of biliary secretion.

Adult↗
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↗
PubMed1983

The determination of thiomalate in physiological fluids by high-performance liquid chromatography and electrochemical detection.

Methods are described for the determination of free thiomalate in the plasma and urine of patients receiving the anti-rheumatic drug sodium aurothiomalate. Thiomalate is separated by reversed-phase chromatography and detected using a gold electrochemical cell. Plasma analyses require maximal sensitivity while urine estimations require selectivity rather than sensitivity: different phosphate buffer-methanol eluents and electrode potentials are used. On-column sensitivity for thiomalate is 40 fmol injected.

Journal Article↗
PubMed1984

Free thiomalate levels in patients with rheumatoid arthritis treated with disodium aurothiomalate: relationship to clinical outcome of therapy.

Sixteen patients with seropositive rheumatoid arthritis were treated with 20 mg disodium aurothiomalate (Myocrisin) weekly for six months. Disease activity was assessed before and after treatment. Plasma profiles and urinary excretion of free thiomalate were measured in all patients after the initial injection and again at six months in the 12 patients remaining on therapy. No difference was found in plasma levels or urinary excretion of free thiomalate between patients who responded to treatment or who developed toxic reactions and those who did not.

Adult↗
PubMed1986

Alterations in macrophage collagenase secretion induced by gold sodium thiomalate.

The effects of gold sodium thiomalate (GST) on the production of specific collagenase by thioglycolate-elicited macrophages was investigated. Our studies demonstrated that GST administration can significantly decrease collagenase production in a dose-dependent manner. These effects were observed with levels of GST attainable in serum or synovial tissue during routine chrysotherapy. In addition, GST altered lysozyme secretion by activated macrophages in a pattern distinct from that of collagenase alteration. These effects of enzyme secretion were not secondary effects of GST on viability, general protein secretion, or the specific assay procedures utilized, and were not attributable to the thiomalate moiety. Thus, GST may exert its therapeutic effect in rheumatoid arthritis through interference with the production of degradative proteolytic enzymes, which are important effector molecules mediating tissue destruction.

Animals↗
PubMed1988

One-year experience in patients treated with auranofin following completion of a parallel, controlled trial comparing auranofin, gold sodium thiomalate, and placebo.

Following a 21-week double-blind trial that compared the effects of treatment with auranofin (AUR), gold sodium thiomalate, and placebo in 193 patients, 147 patients entered a 1-year, open-label study of treatment with AUR (6 mg/day). Results of this open-label study suggest that AUR has a long-term use profile similar to that of other slow-acting antirheumatic drugs. AUR appears to be capable of sustaining an initial response to gold sodium thiomalate. The withdrawal rate remains relatively high: Nearly half of the study patients had discontinued AUR by the end of 1 year.

Adolescent↗
PubMed1988

Peripheral lymphocyte depletion in gold sodium thiomalate-treated rheumatoid arthritis patients.

It has been reported that gold sodium thiomalate treatment of rheumatoid arthritis reduces the number of peripheral blood lymphocytes. In a prospective, double-blind, randomized trial comparing gold sodium thiomalate, auranofin, and placebo in the treatment of rheumatoid arthritis, we investigated absolute lymphocyte counts. We found that peripheral lymphocyte counts decreased, but there was no correlation with clinical change in disease activity.

Arthritis, Rheumatoid↗
PubMedDate not supplied

The pharmacokinetics of intramuscular gold sodium thiomalate in normal volunteers.

Four normal male volunteers participated in a study designed to examine the disposition of gold given intramuscularly as gold sodium thiomalate. Blood samples were collected for 32 days following the administration of 10 mg of gold sodium thiomalate. Plasma gold concentrations were determined by atomic absorption spectrometry. A triphasic decay pattern in plasma gold concentrations was observed. Terminal log-linear phases corresponded to a mean disposition half-life of 25 days. Apparent total body clearance of gold was 7.0 +/- 0.6 ml kg-1 day-1 and the apparent volume of distribution was 0.26 +/- 0.051 kg-1. These pharmacokinetic data are in contrast to previous data from other investigators who have reported half-lives of approximately 5 days. Data from the current study provide a sound rationale for the currently used empiric dosing regimens.

Adult↗
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↗
PubMed1984

Comparative pharmacokinetics of triethylphosphine gold (auranofin) and gold sodium thiomalate (GST).

The pharmacokinetics of gold sodium thiomalate (GST) and triethylphosphine gold (auranofin; AF) are different. Gold sodium thiomalate (GST) is completely bioavailable while only 15-25% of auranofin (AF) is absorbed. Protein binding of AF occurs to a larger extent to macroglobulins than does GST and total body retention of GST is much greater than AF at six months (30% versus approximately 1%). While terminal serum half-lives are approximately equal, total body half-lives are 250 days for GST and 69 days for AF. In addition, excretory pathways contrast markedly, with 85% of AF appearing in the feces while only 30% of GST is excreted by this route; 15% of AF gold appears in the urine and approximately 70% of GST gold is excreted via this route. With all the above differences one would expect that organ and cellular distribution of these compounds would differ. While gold from both drugs is concentrated in kidney, the percent of the dose found in the kidneys is less for AF than GST, at least in animals (0.4% vs 4.8%). Minute quantities are found in other organs but more study is needed to more clearly define organ distribution of these gold compounds, particularly in man.

Absorption↗
PubMed1995

Induction of stress proteins in mouse peritoneal macrophages by the anti-rheumatic agents gold sodium thiomalate and auranofin.

Gold sodium thiomalate and auranofin, anti-rheumatic gold-containing compounds, induced some stress proteins in cultured mouse peritoneal macrophages. The enhanced synthesis of two proteins, heme oxygenase (a 34-kDa protein) and a 23-kDa protein, was particularly prominent. The 23-kDa protein induced by the gold compounds was identical to that found in macrophages exposed to oxidative stress and was suggested to have antioxidant activity. Intraperitoneal injection of gold sodium thiomalate and oral administration of auranofin to mice induced enhanced synthesis of these proteins in peritoneal macrophages analyzed ex vivo. These data suggest that increased synthesis of these proteins may have a role in mediating the pharmacologic effect of these agents.

Animals↗