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PubMed2000

Cytotoxicity and DNA binding properties of a chloro glycylhistidinate gold(III) complex (GHAu).

The chloro glycylhistidinate gold(III) complex (GHAu) is shown to be fairly cytotoxic towards the established A2780 ovarian carcinoma human cell line either sensitive or resistant to cisplatin. Remarkably, GHAu is far more cytotoxic than the corresponding zinc(II), palladium(II), platinum(II) and cobalt(II) complexes implying that cytotoxicity is essentially to be ascribed to the presence of a gold(III) center. Circular dichroism (CD) spectra, atomic absorption measurements and DNA melting profiles suggest that GHAu in vitro is able to bind DNA, the presumed target for several antitumor metal complexes, and to modify its conformation, even if the observed changes are generally small. Implications of these findings for the mechanism of action of cytotoxic gold(III) complexes are discussed.

Animals↗
PubMed1988

High-performance liquid chromatography of bis[1,2-bis-(diphenylphosphino)ethane]gold(I) chloride, a potential antineoplastic agent.

The chromatography of [Au(dppe)2]+ (I), a potential antineoplastic drug, was studied on a variety of stationary phases (ODS Hypersil, PLRP-S, Partisil SAX and Partisil SCX) using aqueous mobile phases containing 60% acetonitrile, 15% tetrahydrofuran and various electrolytes. The effects of both the concentration (0-20 mM) and the nature of the electrolytes, added to the mobile phase, on the chromatography of I were investigated. A wide variety of electrolytes were investigated in which the hydrophobicity of both the anion and the cation were varied. The analyte of interest was found to be unretained by the like-charged Partisil SAX column. On the other hand, I was retained on the Partisil SCX by an ion-exchange mechanism and retention could be controlled by manipulating the electrolyte composition of the mobile phase. I was retained on the two reversed-phase materials by a mixture of solvophobic and electrostatic interactions but, under the conditions studied, the latter mechanism was the dominant one. The retention of I on the two reversed-phase materials was influenced much more by the nature and concentration of the cation added to the mobile phase than it was by the nature and concentration of the anion. Therefore, manipulation of the nature and concentration of the cationic species in the mobile phase appears to afford the most useful means of manipulating the retention of I, and presumably its analogues, on reversed-phase columns.

Antineoplastic Agents↗
PubMed1983

Undecagold labeling of a glycoprotein: STEM visualization of an undecagoldphosphine cluster labeling the carbohydrate sites of human haptoglobin-hemoglobin complex.

A new type of label for electron microscopy has been introduced recently which consists of 11 gold atoms in a compact stable cluster with an organic shell composed of primary amine-substituted phosphine ligands. The radius of the cluster is about 10 A. The (phosphine ligand) amines can be derivatized or allowed to react directly forming covalent bonds to specific sites of other molecules. This report describes the specific labeling of carbohydrate moietis on the glycoprotein human haptoglobin (Hp) in the haptoglobin-hemoglobin complex (Hp X Hb). The Hp X Hb complex is easily recognized in the EM as a barbell-shaped molecule. Only the Hp portion contains carbohydrate (eight carbohydrate chains per Hp X Hb). The carbohydrate moieties of the Hp X Hb complex were oxidized by sodium periodate to produce aldehydes. The primary amines on the undecagold cluster were allowed to react with the aldehyde residues to produce Schiff's base linkages which were subsequently reduced with sodium borohydride. Micrographs obtained on the Brookhaven National Laboratory high-resolution scanning transmission electron microscope (STEM) showed the undecagold label to be localized in a region known to be occupied by the heavy chains of haptoglobin. The amount of labeling was found to be two to four gold clusters per molecule when excess label was reacted. The variation in position of the label is discussed and may be due to flexibility of the carbohydrate chains. Control experiments ruled out nonspecific binding of the gold cluster to the Hp X Hb. The high chemical specificity of the reaction and the high resolution of the gold cluster should make this new label of widespread value in studies of other glycoproteins or carbohydrate-bearing molecules.

Affinity Labels↗
PubMed1997

Treatment of rheumatoid arthritis.

The management of rheumatoid arthritis (RA) remains a challenging objective. Recent trends have led to the earlier and more "aggressive" treatment of patients with active disease. This change in outlook is largely the result of the recognition that significant damage can occur fairly soon after the onset of disease. This article reviews the currently available therapies, including a discussion of the benefits and side effects associated with individual agents. In addition, possible approaches to the treatment of RA will be reviewed.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

Protocol development for combination therapy with disease-modifying antirheumatic drugs.

To date, it has been exceptionally difficult to prove that any combination of disease-modifying antirheumatic drugs is more effective than its components used one at a time. However, only a few of many possible combinations have been evaluated in clinical trials. Careful attention to the details of patient selection, study design and duration, and choice of primary outcome measures is essential. A logical strategy for protocol development emphasizes the use of multiple small pilot studies to screen series of combinations and doses to identify a few that appear to show clinical benefit. The most promising combinations can then be evaluated in large, double-blind, randomized, pivotal studies with a higher probability of success.

Anti-Inflammatory Agents↗
PubMed1993

A disease activity index: its use in clinical trials and disease assessment in patients with rheumatoid arthritis.

Measuring disease activity is important in the assessment of patients with rheumatoid arthritis (RA). The value of composite indices in determining activity is discussed. A validated index, the Stoke index, has been used in clinical trials of combination therapy in patients with RA, both to evaluate efficacy and to stratify response to single-agent therapy before randomization to combination treatment. Disease activity determines the use of disease-modifying antirheumatic drugs. Should these drugs be used in mild RA when disease activity is low? Results of a study comparing hydroxychloroquine with placebo in this situation suggest that they should. Finally, the outcome of suppressing disease activity over a 5- to 10-year period is unknown. Measured either radiologically or functionally, preliminary data suggest that the lower the mean disease activity over time, the more favorable the outcome.

Antirheumatic Agents↗
PubMed2000

Synthesis, crystal structure and antimicrobial activities of two isomeric gold(I) complexes with nitrogen-containing heterocycle and triphenylphosphine ligands, [Au(L)(PPh3)] (HL = pyrazole and imidazole).

Two isomeric gold(I)-triphenylphosphine complexes with nitrogen-containing heterocycles, [Au(L)(PPh3) (HL = pyrazole (1), imidazole (2)) were isolated as colorless cubic crystals for 1 and colorless plate crystals for 2, respectively. The crystal structures of 1 and 2 were determined by single-crystal X-ray diffraction. These complexes were also fully characterized by complete elemental analyses, thermogravimetric/differential thermal analyses (TG/DTA) and FT-IR in the solid state and by solution NMR (31P, 1H and 13C) spectroscopy and molecular weight measurements in acetone solution. These complexes consisted of a monomeric 2-coordinate AuNP core both in the solid state and in solution. The molecular structures of 1 and 2 were compared with those of related gold(I) complexes, [Au(1,2,3-triz)(PPh3)] (3, Htriz = triazole), [Au(1,2,4-triz)(PPh3)]2 (4) as a dimer through a gold(I)-gold(I) bond in the solid state, and [Au(tetz)(PPh3)] (5, Htetz = tetrazole). Selective and effective antimicrobial activities against two gram-positive bacteria (B. subtilis, S. aureus) and modest activities against one yeast (C. albicans) found in these gold(I) complexes 1-4 are noteworthy, in contrast to poor activities observed in the corresponding silver(I) complexes.

Anti-Bacterial Agents↗
PubMed1979

Bis(L-cysteinato)gold(I): chemical characterization and identification in renal cortical cytoplasm.

L-Cysteinatogold(I) was prepared by the reaction of L-cysteine with KAuBr4 in acidic media and its solubility determined from pH 4 to 10. The solubility at pH 7.4 and 37 degrees C is 1 microM. In the presence of excess cysteine, the solubility increases because of formation of bis(L-cysteinato)gold(I). The equilibrium-constant for formation of the bis complex is 2.1 +/- 0.4 X 10(-3), which at pH 7.4 CORRESPONDs to an apparant formation constant of 4.4 X10(4). The formation of the bis adduct was confirmed by chromatographic separation of the products of the reaction between [35S]-L-cysteine and Na2AuTM. This complex elutes with Kav = 1.15 which allows it to be distinguished from other gold thiolates that might form in vivo. The bis(cysteinato)gold(I) complex is shown to be present in kidney cytosol isolated from rats given Na2AuTM in vivo. When additional cysteine is added to the cytosol in vitro, the peak at 1.15 is increased, but if glutathione is added, the low molecular weight gold elutes at Kav = 1.00, which is taken as evidence for the existence of bis(cysteinato)gold(I) in the cytosol preparation. The amount of gold present as bis(cysteinato)gold(I) after 4 different dose schedules has been measured and found to increase with the total cytosol gold concentration. L-Cysteinatogold(I) does not dissolve in the presence of bovine serum albumin to form an adduct.

Animals↗
PubMed1980

Control of intra- and extra-cellular sulphydryl-disulphide balances with gold phosphine drugs: 31P nuclear magnetic resonance studies of human blood.

Contrasting reactions of the antiarthritic complexes ClAuPEt3 and ClAu(PEt3)2 with blood have been studied by 31P nmr spectroscopy. The monophosphine complex has two binding sites in erythrocytes, probably at the SH groups of glutathione and haemoglobin. The bis complex solidifies blood via a reductive denaturation of albumin, with the release of OPet3.

Disulfides↗
PubMed2001

Structural characterization and cytostatic activity of chlorobischolylglycinatogold(III).

Based on the ability of bile acids for vectorializing the cytostatic activity of other agents, we have designed and synthesized a new bile acid cholylglycinato Au(III) complex, named Bamet-A1. It has been characterized by means of EA (elemental analysis), FT-IR, NMR, FAB-MS (fast atom bombardment-mass spectrometry) and Vis-UV techniques. This characterization allowed us to propose a structure of the type [Au CG(O) CG(N,O) Cl] for the neutral complex, which has the composition C522H84N2O12AuCl and is very soluble in water, methanol, ethanol and DMSO (dimethylsulfoxide). The study in aqueous solution suggested a redox process for its transformation, which is accompanied by the appearance of colloidal gold phase. The behavior in 4 mM NaCl water (in order to mimic the cytoplasmatic fluid) was similar to that observed in water, while in a 150 mM NaCl (similar to extracellular fluid and serum), the apparition of a dark blue precipitate was observed. This complex displays fluorescence, which does not change when incubated with DNA obtained from E. coli. Bamet-A1 was found to inhibit the growth of a variety of cell lines. The cytostatic effect was mild against human hepatoma HepG2, mouse hepatoma Hepa 1-6, rat hepatoma McA RH-7777 and human colon adenocarcinoma LS-174T, and stronger against mouse sarcoma S180-II and mouse leukemia L-1210 cells. The appearance of colloidal Au during the process of hydrolysis under physiological conditions may explains the low cytostatic activity.

Animals↗
PubMed2002

(13)C, (31)P and (15)N NMR studies of the ligand exchange reactions of auranofin and chloro(triethylphosphine)gold(I) with thiourea.

The interaction of thiourea (Tu) with auranofin (Et(3)PAuSATg) and its analogue, Et(3)PAuCl has been studied using (13)C, (31)P and (15)N NMR spectroscopy. It is observed that Tu is able to replace both the ligands, Et(3)P and SATg(-) simultaneously from gold(I) in auranofin, forming [Et(3)P-Au-Tu](+) and Tu-Au-SATg complexes. However, no separate resonances for these species were observed either due to their rapid exchange with auranofin and thus giving only the average resonances or because the chemical shifts of either two species are same so that they cannot be resolved. The displaced SATg(-) is oxidized to its disulfide, (SATg)(2). However, some of the displaced Et(3)P is oxidized to Et(3)PO while the remaining reacts with Tu to form Et(3)P-Tu species, characterized by delta 31P of 1.0 ppm, assigned after an independent reaction between Et(3)P and Tu. In an experiment using a 0.05 M solution of auranofin, the Et(3)PO resonance appeared in auranofin spectrum after 4 days of addition of 1.0 equivalent of Tu, showing that the reaction is slow. A resonance for free Et(3)P is also detected in 31P NMR on the addition of CN(-). It is also observed that Tu reacts with Et(3)PAuCl to form [Et(3)P-Au-Tu](+) via displacement of Cl(-), consistent with an upfield shift of 6.2 ppm in >C [double bond] S resonance of Tu in (13)C NMR. In (15)N NMR, a smaller downfield, instead of an upfield shift, in NH(2) resonance of Tu on its addition to auranofin and Et(3)PAuCl indicates that it is not binding to gold(I) through nitrogen.

Antirheumatic Agents↗
PubMedDate not supplied

[Iatrogenic neuropathies].

During the last few years the list of drugs capable of inducing a iatrogenic neuropathy has been considerably lengthened. Drug toxicity to peripheral nerves may be discovered at the experimental stage, but it is usually recognized after the drug has been launched on the market, hence the importance of pharmacovigilance. The responsibility of a drug for the occurrence of neuropathy may be difficult to prove, particularly when the drug is used in the treatment of a disease which, by itself, may be responsible for a lesion of the peripheral nervous system. Iatrogenic neuropathies are usually axonal, but some drugs produce a primary disorder in the myelin-Schwann cell couple. Schwann cell diseases may be induced by drugs, such as perhexiline maleate, amiodarone or chloroquine, which inhibit lysosomal enzyme activity. In such cases inclusions representing fat-loaded lysosomes can be detected in various tissues, and particularly in Schwann cells. In certain patients, notably those treated with gold salts, an immune mechanism might be responsible for neuropathy. Most drug-induced neuropathies are due to a primary lesion of the neuron which is more often an axonopathy than a neuronopathy. It is usually a retrograde distal axonopathy the occurrence of which is attributed to a disorder of the fast retrograde axonal flow. In a few cases, the finding of a biochemical mechanism perturbing the axonal flow may help in preventing the occurrence of a iatrogenic neuropathy.

Amiodarone↗
PubMedDate not supplied

[Renal microscopic hematuria in rheumatoid polyarthritis].

In a retrospective study of 162 cases of rheumatoid arthritis we found that 24 patients (14.8%) had presented with microscopic haematuria with or without proteinuria. Renal biopsy had been performed in 15 of these 24 patients. Apart from the classical lesions of extramembranous glomerulonephritis, amyloidosis and interstitial nephritis, 60% of histological results showed lesions of mesangial glomerulonephritis. These lesions seemed to be independent of maintenance treatments, but they might have been facilitated by the chronic inflammation kept going by the rheumatoid disease itself.

Adult↗
PubMed1999

[Complications of colonic diverticular disease during rheumatoid polyarthritis: 7 cases].

INTRODUCTION: Among the gastrointestinal adverse effects of nonsteroidal anti-inflammatory drugs (NSAID) and corticoids are mentioned complications of colonic diverticular disease. However, very few studies have described their consequences in rheumatoid arthritis. EXEGESIS: We report on seven patients who were admitted in our department between 1984 and 1997. All patients received corticoids and another antirheumatic drug (gold salts, hydroxychloroquine, immunosuppressive drugs); treatment also included NSAID in four cases. Two patients had a necrotizing vasculitis accompanying rheumatoid arthritis. Intestinal accompanying diseases were the following: one diverticulitis, three colonic perforations with pelviperitonitis, one colovesical fistula, one pelvic abscess, and one diverticular hemorrhage. All patients underwent surgery with positive results. CONCLUSION: Combination of the four following symptoms: fever, abdominal pain, diarrhea, and hemorrhage, can uncover a complication of colónic diverticular disease occurring in the course of rheumatoid arthritis. It should be investigated, even if no history of diverculosis may be evidenced.

Abscess↗
PubMed2004

Infiltrative lung disease due to noncytotoxic agents.

Pulmonary complications of therapy for RA or other benign conditions are often difficult to diagnose and treat. Clinical presentation of lung disease that is due to noncytotoxic drugs may vary from a mild, nonspecific cough to fulminant respiratory failure. The differential diagnosis of pulmonary disease should include drug toxicity, progression of the primary illness, and opportunistic infection. An objective assessment of the patient's baseline pulmonary status, as well as his treatment history, is crucial to differentiate drug-induced pathology from the primary process. Diagnostic work-up should include chest radiograph, repeat pulmonary function testing, and high-resolution CT of the chest. Bronchoscopy for tissue pathology or specific BAL cytokine markers also may yield useful information; occasionally, open-lung biopsy is required. If pulmonary disease that results from noncytotoxic drug therapy is suspected, the drug should be discontinued until the disease process is understood clearly.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2003

Neonatal tolerance to a Th2-mediated autoimmune disease generates CD8+ Tc1 regulatory cells.

Immunological tolerance can be achieved in animals by exposure of newborn to a foreign antigen. Depending on the dose and timing of the antigenic challenge, tolerance has been reported to result in clonal deletion, anergy or active suppression. In this latter case, regulatory T cells prevent autoimmunity by suppressing the reactivity of pathogenic self-reactive T cells. We have previously reported the generation of a neonatal, mercury-specific, and dominant tolerance to autoimmunity induced by mercury salts in rats. Chronic exposure to mercury salts can lead to SLE-like autoimmune responses, mediated by autoreactive CD4+ Th2 cells, that regulate and are followed by a resistant state mediated by protective CD8+ T cells. The aim of the study was to compare the resistance to the neonatal tolerance to mercury disease, and to further characterize the CD8+ T cells endowed with regulatory capacity in the neonatal tolerance model. We report here that resistance to mercury disease is long lasting and not mercury-specific, suggesting that different CD8+ T cells are involved in resistance and neonatal tolerance, and that regulatory CD8+ Tc1 cells generated in tolerance are required to control the CD8- cell population from developing Th2-mediated autoimmunity. Upon mercury recall, CD8+ CD45RC(high) T cells, that represent the Tc1 subset in the rat, expanded and were polarized towards IFNgamma production. Interestingly, identical results were obtained with the CD8+ CD25+T cell population. Substantial amounts of FasL gene expression were detected in CD8+ T lymphocytes upon recall with the tolerogen. AICD may be one of the regulatory mechanisms used by these regulatory CD8+ Tc1 cells that control neonatal tolerance to a Th2-mediated autoimmune disorder.

Adoptive Transfer↗