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At least 19 recordsLinked to original sources
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↗
PubMed1977

Inhibition of antigen- and mitogen-induced human lymphocyte proliferation by gold compounds.

Gold sodium thiomalate (GST) inhibited in vitro antigen- and mitogen-triggered human lymphocyte DNA synthesis. Inhibition of responsiveness was observed with concentrations of GST equivalent to gold levels found in serum or tissues of patients receiving chrysotherapy, Inhibition was dependent upon the gold ion itself since GST and gold chloride were both inhibitory whereas thiomalic acid was not. Inhibition could not be explained by nonspecific killing of cells or by an alteration in the kinetics of the responses. GST inhibited mitogen-induced proliferation most effectively when present from the initiation of culture and could not inhibit the responsiveness of cells which previously had been activated by concanvalin A. These findings indicated that GST blocked a critical early step in lymphocyte activation. The degree of GST-induced inhibition of proliferation was increased in cultures of cells partially depleted of monocytes. Moreover, inhibition was reversed by supplementation of these cultures with purified monocytes. These observations suggested that GST blocked thymus-derived (T)-lymphocyte activation by interfering with a requisite function of the monocyte population in initiating such responses. Prolonged incubation of peripheral blood mononuclear cells with GST resulted in diminished mitogen responsiveness upon subsequent culture in the absence of gold. The addition of fresh monocytes restored responsiveness to these populations. Furthermore, preincubation of purified monocytes with GST rendered them deficient in their ability to support mitogen-induced T-lymphocyte proliferation on subsequent culture. These observations indicate that the major effect of GST results from interference with the functional capability of the monocyte population.

Antigens↗
PubMed1979

Inhibition of pokeweed mitogen-induced immunoglobulin production in humans by gold compounds.

The effect of gold compounds on an in vitro model of antibody production was investigated. Peripheral blood mononuclear cells from healthy adult individuals were stimulated with pokeweed mitogen (PWM) and generation of immunoglobulin secreting cells (ISC) was assayed. Addition of gold sodium thiomalate 10 microgram/ml markedly inhibited mitogen-induced ISC production. The suppression of Ig production could not be explained by nonspecific lymphocyte toxicity or interference with the assay system. Inhibition of PWM responsiveness was mediated directly by the gold moiety and was not a function of the thiomalate. Furthermore, it was shown that maximum suppression of ISC generation occurred only when gold was added to cultures within the first 24 hours of incubation. This suggested that gold compounds inhibit an early step in B cell activation and differentiation rather than merely blocking Ig secretion by mature plasma cells.

Antibody-Producing Cells↗
PubMed1977

Aurosomes produced in the synovial membrane by the oral administration of a gold compound SK & F 36914.

Chlorotriethylphosphine gold (SK & F 36914) administered orally to rabbits produced aurosomes in the synovial membrane. These aurosomes were similar to aurosomes produced by parenteral or intra-articular injections of soluble gold salts such as sodium aurothiomalate and aurothioglucose. This study shows, (1) that an orally administered gold compound is capable of producing gold deposits in the synovial membrane, and (2) that such compounds may have a future in the treatment of rheumatoid arthritis.

Administration, Oral↗
PubMed1977

Gold compounds in rheumatoid arthritis. Report of a symposium.

A vast accumulation of clinical experience and controlled studies justifies the use of gold compounds in selected cases of rheumatoid arthritis. The striking therapeutical efficacy observed in some patients has stimulated active research to clarify the pharmacokinetics and mechanisms of action of gold compounds. Based on this knowledge, the possibility of selecting gold-responsive patients may be enhanced, and the frequency of adverse reactions decreased. Liberal indications and inexperience in administration and control have given gold therapy mixed reputation. A symposium in Umeå, Sweden, summarized present knowledge and current concepts among Scandinavian rheumatologists on the rational use of gold compounds.

Arthritis, Rheumatoid↗
PubMed1992

Helicobacter pylori seroprevalence in patients with rheumatoid arthritis: effect of nonsteroidal anti-inflammatory drugs and gold compounds.

PURPOSE: To investigate the relationship between Helicobacter pylori infection and nonsteroidal anti-inflammatory drug (NSAID) intolerance and the effect of gold use on the seroprevalence of H. pylori. PATIENTS AND METHODS: We examined the frequency of discontinuation of NSAIDs in 132 unselected patients with rheumatoid arthritis attending an outpatient subspecialty clinic, and the effect of gold compound use on the seroprevalence (by IgG enzyme-linked immunosorbent assay) of H. pylori infection in this population. Logistic and multivariate regression analysis was performed adjusting for age, gender, ethnic origin, history of ulcer, and duration of rheumatoid arthritis. RESULTS: Fifty-four patients had a positive serology for H. pylori (41%). Twenty-seven of the seropositive patients (50%), versus 45 of the seronegative patients (57.7%), had to discontinue NSAIDs (aspirin and/or nonaspirin) at least once since their diagnosis of rheumatoid arthritis because of gastrointestinal side effects (odds ratio [OR], 0.93; 95% confidence interval [CI], 0.63 to 1.38). Forty-one of the seropositive patients (76%) had received gold compounds as compared with 62 of the seronegative patients (79.5%) (OR: 0.96; 95% CI: 0.61 to 1.50). CONCLUSION: We did not find any relationship between H. pylori seropositivity and NSAID intolerance in patients with rheumatoid arthritis. In addition, our results do not demonstrate a reduction in H. pylori seroprevalence in rheumatoid arthritis patients treated with gold compounds.

Aged↗
PubMed1992

Effect of gold compounds on the activity of adenylyl cyclase in human lymphocyte membranes.

OBJECTIVE: To determine the effects of aurothioglucose, aurothiomalate, and auranofin on basal and forskolin-activated adenylyl cyclase activity in human total lymphocyte membranes, and in membranes of T and B lymphocyte subsets. METHODS: Membranes were isolated from human total lymphocytes and T and B cell subsets. The effects of gold compounds on basal and forskolin-stimulated activity of adenylyl cyclase were measured by radioassay. RESULTS: The gold compounds inhibited adenylyl cyclase activity. This inhibitory effect required the presence of both the sulfhydryl ligands and aurous cation. CONCLUSION: Regulation of lymphocyte adenylyl cyclase by gold compounds represents a potential mode of action of these drugs in rheumatic diseases.

Adenylyl Cyclases↗
PubMed1976

Auranofin. New oral gold compound for treatment of rheumatoid arthritis.

Eight patients with rheumatoid arthritis were treated with SK & F D-39162 (auranofin), a new oral gold compound which was effective in suppressing adjuvant-induced arthritis in rats. Clinical and humoral parameters were studied during a 3-month period of drug administration followed by a 3-month period under placebo. The drug was absorbed, well tolerated, and its action was manifested by a drop in the mean IgG blood levels in the third week of treatment accompanied by clinical improvement after 5 weeks of oral gold intake. Together with IgG changes, an increase of the albumin ratio was observed, as well as a decrease of alpha2-globulin and rheumatoid factor titres. From a total number of 60 swollen joints found initially in the 8 patients only 17 were swollen at week 12 and 9 at week 15. Although the number of patients treated was too small to allow definite conclusions, a follow-up study under placebo of clinical and laboratory changes in the same patients during another 3-month period showed that IgG serum levels rapidly reverted preceding a flare up of disease activity after withdrawal of the drug. This confirmed a direct role in cause-effect relation played by the new oral gold compound.

Adult↗
PubMed1992

[Gold compounds and D-penicillamine for therapy of rheumatoid arthritis].

Rheumatoid arthritis is a severe disease and it is difficult to prevent the progression of disease. Gold compounds (injectable gold and oral gold) and D-penicillamine (D-PA) have the possibility to retard joint destruction and to slow radiological progression. These drugs are called Disease Modifying Antirheumatic Drugs (DMARD), and they should be tried in cases resisting conventional NSAID's therapy. They are effective in more than 60% in severe rheumatoid patients but they also have many side effects, e.g. eczema, skin rash, renal dysfunction, aplastic anemia. Laboratory checks should be carried out once a month during the first six month, and every 2 or 3 months thereafter. To compare injectable gold with D-PA, discontinuation due to inefficacy of D-PA is higher than with injectable gold, but side effects of injectable gold is greater. Oral gold is less effective than the other 2 drugs, but has a lower rate of side effects.

Arthritis, Rheumatoid↗
PubMed1979

Metabolism and distribution of gold compounds.

The pharmacokinetics of gold in blood and urine are compared during intramuscular and oral chrysotherapy for rheumatoid arthritis. Blood gold levels are 3 to 10 fold higher with injectable aurothioglucose and gold sodium thiomalate (50 mg/week) than with oral auranofin (6 mg/day). But, the serum half-life of the parenteral compounds is significantly shorter (5.5 days) than the oral agent (14-21 days). The gold content of urine is nearly 10 times higher with the intramuscular compounds than with the oral drug. The excretory pathways and tissue distribution of gold during conventional intramuscular chrysotherapy are reviewed. Forty percent of a 50 mg injection of gold sodium thiomalate is excreted in 7 days, of which 70% is recovered in the urine. Highest gold concentrations are found in the reticuloendothelial system, adrenal glands and kidneys, while the bone marrow, liver, skin and bone contain the greatest quantities of gold.

Animals↗
PubMed1979

Inhibitory effects of a new oral gold compound on HeLa cells.

Auranofin (AF), a recently introduced oral antirheumatic coordinated gold compound, was investigated for its antitumor potential. Due to certain similarities with the antitumor-coordinated compound, cis-Diamminedichloroplatinum II, we studied the effects of AF on cell proliferation. These studies included assessing DNA, RNA, and protein synthesis as measured by incorporation of 3H-thymidine, 3H-uridine, and 3H-leucine, respectively, into HeLa cells. AF was shown to exert a dose-dependent inhibition on DNA synthesis and to inhibit 3H-thymidine uptake more rapidly and persistently than 3H-uridine or 3H-leucine uptake at a gold concentration of 75--100 micrograms/dl. These three parameters were inhibited with a 24-hour exposure to 100 micrograms/dl. The inhibition of 3H-thymidine uptake in HeLa pretreated for 6 hours with 50 or 100 micrograms/dl of gold was found to be irreversible. No change in tracer uptake was observed in the acid-soluble pool or in the uptake of 3H-2-deoxy-D-glucose in these cells. Furthermore, HeLa cells demonstrated marked reductions in viability and oxygen uptake after exposure to AF. Dose-dependent surface morphological changes, e.g., blebbing, pitting, were noted in these cells after a brief treatment period. These results suggest this coordinated gold compount exerts a significant inhibitory effect on essential biological processes and functions.

Aurothioglucose↗
PubMedDate not supplied

Methyl ester of N-formylmethionyl-leucyl-phenylalanine: chemotactic responses of human blood monocytes and inhibition of gold compounds.

N-formylmethionyl-leucyl-phenylalanine, a potent hemotactic peptide for human polymorphonuclear leukocytes, is less chemotactic for human blood monocytes. Esterification of the N-formylated tripeptide enhances its chemotactic activity for monocytes by more than 4 logs, whereas a decrease by 3 logs is observed for polymorphonuclear leukocytes. These results indicate the participation of the C-terminal carboxyl group in chemotaxis of different cell types. We have also observed the selective inhibition of chemotactic responsiveness of human blood monocytes by a clinically useful antirheumatic drug, sodium aurothiomalate. Since this is the first in vitro cell migration model of inflammation in which gold compounds have demonstrated activity in micromolar concentrations, it suggests a site of action for this antirheumatic drug.

Chemotaxis, Leukocyte↗
PubMed1979

Acquired epidermolysis bullosa treated with a gold compound.

A 20-year-old man with acquired epidermolysis bullosa of 3 years' duration was treated intramuscularly with gold sodium thiomalate. After a total dose of 1 000 mg gold sodium thiomalate, administered over a period of 9 months, the patient has shown an almost complete remission, without any apparent side effects of the chrysotherapy.

Adult↗
PubMed1976

Management of pemphigus with gold compounds: a long-term follow-up report.

Fourteen of 15 patients with pemphlgus have responded successfully to systemically administered gold therapy for up to four years. Eight of the 15 (56%) are in remission, requiring no therapy (mean, 21 months). The remaining seven patients are receiving maintenance systemic gold therapy. Only one instance of toxicity was seen during maintenance therapy. The high remission rate associated with gold therapy and the infrequent side-effects during maintenance therapy suggest that systemically given gold therapy may be the treatment of choice for the management of pemphigus, following initial therapy with corticosteroids when necessary.

Adult↗