The suitability of multi-metal clusters for phasing in crystallography of large macromolecular assemblies.
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Crystallography↗
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The structural flexibility of ferric cytochrome c: regulation of the spin-state equilibrium by an anti-arthritic gold(I) compound at neutral pH.
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Animals↗
Cholestasis and pneumonitis induced by gold therapy.
The authors describe the association of gold salt-induced cholestasis and lymphocytic alveolitis proved by liver biopsy and broncho-alveolar lavage. To our knowledge this is the third case report on the combination of liver disease and pulmonary infiltration induced by gold compounds.
Aged↗
Inhibition of human phospholipase C by aurothiomalate and (triethylphosphine) gold complexes.
The effect of several gold complexes on the activity of phospholipase C from human blood platelets was studied in vitro. Aurothiomalate and auranofin--2 agents used for the chrysotherapy of rheumatoid arthritis--, gold chloride, (triethylphosphine)gold chloride, and 5 newly synthesized (triethylphosphine)gold complexes dose-dependently inhibited the enzyme with IC50 values between 0.8 mumol/l ((triethylphosphine)gold chloride) and over 100 mumol/l (auranofin). None of the compounds affected phospholipase A2 from human polymorphonuclear leukocytes at concentrations up to 100 mumol/l. Inhibition of phospholipase C by (triethylphosphine)gold chloride, aurothiomalate, and compound 3 was not significantly different at substrate concentrations of 20 and 100 mumol/l phosphatidylinositol, suggesting that these gold complexes do not inhibit phospholipase C by competing with the substrate. After confirming the Ca2+ dependence of the human platelet phospholipase C by demonstrating inhibition by the Ca2+ chelators EDTA and EGTA--but no inhibition by the Zn2+ chelator 1,10-phenanthroline--the inhibition of the enzyme by (triethylphosphine)gold chloride, aurothiomalate, and compound 3 was studied at 3 different concentrations of Ca2+ in the range of 0.2 to 2 mmol/l. Inhibition by (triethylphosphine)gold chloride was not affected by changes of Ca2+, whereas inhibition by aurothiomalate and compound 3 was markedly suppressed by increasing the Ca2+ concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
Antirheumatic Agents↗
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↗
Effects of gold compounds on the function of phagocytic cells. II. Inhibition of superoxide radical generation by tripeptide-activated polymorphonuclear leukocytes.
The effect of sodium aurothiomalate and triethylphosphine gold on the generation of superoxide radicals by chemotactic tripeptide-activated polymorphonuclear leukocytes has been investigated using a cytochrome C reduction technique. Neither gold compound inhibited the binding of the tripeptide to cells. Sodium aurothiomalate in concentrations ranging from 1 to 100 micrograms/ml produced mild, nonsignificant inhibition of the generation of superoxide radicals. In contrast, triethylphosphine gold at a concentration of 0.25 microgram/ml was associated with a mild enhancement of superoxide radical production, but the enhancement was not statistically significant. At concentrations of 1.25 micrograms/ml and above, there was a profound inhibition of superoxide radical production by these activated cells. Since the products of the respiratory burst, including superoxide, are thought to be inflammatory mediators, it is postulated that the inhibition of superoxide radical generation by gold compounds may be another mechanism by which the compounds modulate their antiinflammatory effects in patients with rheumatoid disease.
Binding Sites↗
Synthesis of thionato(triethylphosphine) gold(I) complexes:analogues of "auranofin," an antiarthritic drug.
New compounds having the formula [L-Au-PEt3]Cl (where L = imidazolidine-2-thione(Imt) and 1,3-Diazinane-2-thione(Diaz)) are synthesized. They are characterized by elemental analysis, infrared, 13C and 31P NMR spectroscopy.
Antirheumatic Agents↗
Responses of the colonic epithelium to auranofin: evidence for involvement of enteric nerves.
Auranofin, the orally effective gold compound, stimulated the canine colonic epithelium in vitro. It increased short circuit currents across both the innervated mucosal and functionally "nerve-free" epithelial preparation, when added to either the luminal or serosal solutions. Serosal responses were inhibited by tetrodotoxin (TTX). A hydrophilic gold compound, sodium aurothiosulphate produced similar effects but only on serosal addition. Gold compounds can thus alter colonic transport activating enteric nerves and releasing a neurotransmitter. Thus gold induced diarrhea could have a significant neural component.
Animals↗
Injectable gold compounds: an overview.
Injectable gold compounds have enjoyed widespread, but occasionally controversial, use in rheumatoid arthritis since the 1920s. This overview examines the data from controlled trials and longer-term observational studies. We conclude that gold is equivalent to other widely used second-line agents in terms of efficacy. Toxicity profiles are similar, apart from methotrexate. It is most efficacious and toxic in the first 2 yr of treatment. There appears to be a dose-response relationship for both efficacy and toxicity. Gold is one of the few agents that decreases the rate of progression of erosions (RR 0.38, 95% CI 0.23-064). Gold compounds, therefore, have a definite place in the rheumatologist's armamentarium, but further research is required to determine optimal monitoring regimes as well as the role of maintenance therapy and combination therapy.
Antirheumatic Agents↗
Effect of gold compounds on phorbol myristic acetate (PMA) activated superoxide (O2-) production by mouse peritoneal macrophages.
A number of gold compounds, nonsteroidal antiinflammatory drugs (NSAID) and protease inhibitors have been examined for their ability to inhibit the respiratory burst of peritoneal macrophages. A potent (IC50 = 5 microM or less) dose dependent inhibitory activity was seen with a number of triethylphosphine gold I ( TEPG ) compounds. Nonphosphine gold compounds were less active. The ligands of TEPG were inactive. Several NSAID stimulated the respiratory burst, whereas 2 protease inhibitors tested were inhibitory. The structure activity relationship of TEPG is also presented.
Animals↗
Cellular interactions of auranofin and a related gold complex with RAW 264.7 macrophages.
Auranofin (AF) is an orally active chrysotherapeutic agent whose precise mechanism of action with its putative target cell, the macrophage, is not known. In a previous paper, we described a sequential thiol exchange mechanism that explained auranofin's molecular mechanism of interaction with RAW 264.7 cells. To further understand the mode of action of AF and to test the validity of the thiol exchange model, we have continued to study the interactions with macrophages of AF and a related gold complex, triethylphosphine gold chloride (TEPG). Evaluation of the effects of AF and TEPG on RAW 264.7 cells demonstrated that: more gold from TEPG than AF associated with cells over time and with a variety of concentrations; and cellular association of AF and TEPG was temperature dependent. The energy of activation for cell association, the rate-limiting step in the thiol exchange process, was lower for TEPG than AF; cellular association and uptake of both compounds did not require metabolic energy; and efflux of both AF and TEPG was time, temperature, and thiol dependent. Based on these and previous data, we conclude that sequential thiol exchange may be a generic phenomenon for cellular uptake and distribution of thiol reactive gold compounds and that the rate-limiting step is the exchange of either tetraacetylthioglucose (TATG) or chloride for a membrane-localized sulfhydryl group.
2,4-Dinitrophenol↗
[Toxic glomerulonephritis].
Most glomerulopathies are immunologically-mediated. Their pathogenesis is now better understood. The role of cell-mediated immunity has recently been envisaged. The role of circulating antibodies now seems to be more important than that of circulating immune complexes. Antibodies may recognize structural or "planted" antigens in the kidney, the latter being non-renal molecules that may bind renal structures for non-immune reasons. The linear or granular pattern observed at immunofluorescence depends upon the regular or irregular distribution of the antigen. In susceptible individuals, various toxins (heavy metals such as mercury or gold, drugs with an SH group, non-steroidal anti-inflammatory agents) may induce an immune glomerulopathy. It has recently been shown that Brown-Norway rats exposed to one of the above-mentioned agents develop anti-self class II T lymphocytes that are responsible for a polyclonal activation of B cells. Among the various autoantibodies that are produced, some have a nephritogenic potential. Other drugs are responsible for glomerular lesions due to a direct toxic effect of the compound. Doxorubicin induces a nephrotic syndrome in the rabbit, while mitomycin induces a haemolytic uraemic syndrome in humans. Finally, drug addiction often leads to glomerulosclerosis.
Animals↗
Metal compounds in therapy and diagnosis.
There is increasing interest in the use of metal-containing compounds in medicine. This review describes several therapeutic applications, such as the use of platinum complexes in cancer chemotherapy, gold compounds in the treatment of arthritis, gallium in hypercalcemia, bismuth in anti-ulcer medication, and sodium nitroprusside in hypertension. The use of metal radionuclides in diagnosis and radiotherapy and the role of paramagnetic metal complexes as contrast agents in magnetic resonance imaging are also discussed.
Anti-Ulcer Agents↗
Mechanisms of action of slow-acting drugs in rheumatoid arthritis.
Slow-acting anti-rheumatic drugs exhibit a number of similar properties in treated patients that suggest that they may have a common mode of action in rheumatoid arthritis. In vitro evaluation of drug action suggests that each of the slow-acting agents possesses immunosuppressive activity that may explain its therapeutic efficacy in rheumatoid arthritis. Even though these agents appear to be able to suppress immune responses, the site of action of these agents differs. Thus, gold compounds and the antimalarials suppress the activity of mononuclear phagocytes, whereas D-penicillamine and other thiol-containing slow-acting agents inhibit the activity of helper T cells. These agents may therefore be effective by interfering with various specific aspects of the immunologic reactivity that drives the chronic inflammation of rheumatoid arthritis.
Anti-Inflammatory Agents, Non-Steroidal↗
Biospecific labeling with undecagold: visualization of the biotin-binding site on avidin.
The biotin-binding site on avidin has been labeled with biotin conjugated to undecagold, an organometallic cluster compound containing 11 gold atoms in a core angestroms in diameter. Examination of unstained specimens by scanning transmission electron microscopy reveals the labeled sites directly, without computational averaging or filtering of the images. This approach should be widely applicable for determining the locations of subunits and functional site in biological macromolecules at a resolution at a resolution in range of 15 angstroms.
Avidin↗
Goldsalts, levamisole and D-penicillamine as first choice slow-acting antirheumatic drugs in rheumatoid arthritis--a long-term follow-up study.
In the present study, 345 rheumatoid arthritis patients were treated using goldsalts, D-Penicillamine or levamisole as the slow-acting antirheumatic drug of first choice. Goldsalts were given to 182 patients, levamisole to 139 and D-Penicillamine to 24. At the time of the present evaluation, 83 patients were still on goldsalts (44.6%), 63 on levamisole (45.2%) and 11 on D-Penicillamine (45.9%). Adverse reactions required interruption of treatment in 64 patients on goldsalts (35.2%), in 44 on levamisole (31.7%) and in 5 on D-Penicillamine (20.8%). Inefficacy was responsible for withdrawal of 33 patients receiving goldsalts (18.1%), 30 receiving levamisole (21.6%) and 8 receiving D-Penicillamine (33.3%). The duration of treatment was 4.6 years for goldsalts, 3.6 years for levamisole and 3.6 years for D-Penicillamine. In the present analysis none of the compounds was found to have a definite advantage over the others. The rather favourable treatment continuation rates in this study can be attributed to the fact that the slow-acting antirheumatic drugs were given at an early stage of the disease, preferably before the occurrence of radiological lesions.
Adult↗
[Possible role of cellular immunity against tubular basement membrane antigen (TBM) in gold nephropathy in rheumatoid arthritis patients].
Autoantibody formation and lymphocytes proliferative response to tubular basement membrane (TBM) antigen were examined to clarify the pathogenesis of gold nephropathy, in rheumatoid arthritis patients. The existence of tubulopathy was ascertained by urine protein analysis, electrophoresis and urine TBM antigen titration. Circulating antibody to human TBM antigen titrated by enzyme immunoassay was significantly elevated in patients with gold tubulopathy, and mitogenic stimulation with TBM antigen of peripheral lymphocytes specifically responded in the early stage after receiving gold, but then clearly decreased after the cessation of gold. But, when the lymphocytes had been passed through a nylon wool column, the reaction was remarkably high even in the later stage after receiving gold, suggesting that another suppressive population of lymphocytes became trapped in the nylon wool column. This evidence suggests that gold compounds definitely act as initiating and promoting agents, and the development of tubular disorders induced by gold are likely related to the cellular recognition of effector T cells to the TBM antigen, following the strong effect of gold on the cellular immune system.
Adult↗
Labeling with nanogold and undecagold: techniques and results.
A significant new development in gold labeling for microscopy has been achieved through the use of gold cluster compounds that are covalently attached to antibodies or other probe molecules. These unique gold probes are smaller than most colloidal gold conjugates and exhibit improved penetration into tissues, higher labeling densities, and allow many new probes to be made with peptides, nucleic acids, lipids, drugs, and other molecules. A new fluorescent-gold conjugate is useful for examining localization by fluorescence microscopy, then visualizing the same label at the ultrastructural level in the electron microscope.
Animals↗