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PubMed1996

Antitumor properties of some 2-[(dimethylamino)methyl]phenylgold(III) complexes.

Four analogues of the gold(III) complex [AuCl2(damp)] (1) (damp = 2-[(dimethylamino)methyl]phenyl) have been evaluated for antitumor activity. The compounds have structural features in common with cisplatin which was included as a comparison in the study. In vitro, against a panel of cell lines established from tumors of different tissue types, the gold complexes showed broadly similar growth inhibitory properties with some selectivity to the HT1376 bladder cell line. In a panel of human ovarian carcinoma cell lines, non-cross-resistance to cisplatin was observed, for the complexes, in an acquired cisplatin-resistant line. In vivo, using subcutaneously implanted xenografts derived from the HT1376 bladder and CH1 ovarian cell lines, [Au(acetato)2(damp)] (3) and [Au(malonato)(damp)] (5) (administered intraperitoneally) gave significant tumor inhibition. Mechanistic studies performed with compound 3 showed marked differences to cisplatin. Thus, much higher concentrations of the gold compound were required to affect Col E1 plasmid mobility, and an alkaline elution study showed that 3 did not cause interstrand DNA cross-links in SK-OV-3 cells. Exposure of SK-OV-3 cells to 3 induced only relatively minor changes in cell cycle distribution. Furthermore 3 was only marginally active in vivo against the cisplatin-sensitive murine ADJ/PC6 plasmacytoma. In summary, the gold-(III) complexes 3 and 5 exhibited selective cytotoxicity in vitro and showed in vivo antitumor activity against human carcinoma xenografts. Also, although 3 has some structural similarity to cisplatin, its mode of action appears to be different.

Animals↗
PubMed1989

Mechanism of inhibition of human neutrophil collagenase by Gold(I) chrysotherapeutic compounds. Interaction at a heavy metal binding site.

The mechanism of inhibition of two forms of human neutrophil collagenase (HNC) by six Au(I) compounds, some of which are used as chrysotherapeutic agents, has been investigated. The two forms of enzyme studied are active and latent HNC, the latter of which is activated by p-chloromercuribenzoate (PCMB). The effects of PCMB and Zn(II), which are normally included in the assays, on the activity of both forms of HNC and on their inhibition by these Au(I) compounds have also been studied. Zn(II) stimulates the activity of both the active and PCMB-activated latent forms of HNC up to a concentration of 50-100 microM, after which it inhibits markedly. PCMB activates latent HNC up to a concentration of 100 microM followed by inhibition at higher concentrations. Active HNC is not stimulated at PCMB concentrations below 100 microM, but is inhibited at higher concentrations. The stimulatory effects of Zn(II) and PCMB on HNC and its inhibition by PCMB are all attributable to binding at distinct sites. The inhibition of both active and PCMB-activated latent HNC by the Au(I) compounds is noncompetitive and is reversed by Zn(II). The inhibition of both forms of HNC by SKF 80544 and SKF 36914, which do not contain thiol ligands, is weak to moderate and is not influenced by the PCMB concentration. In contrast, PCMB markedly enhances the inhibition by Myocrisin, Sanocrisin, and Solganol by complexing to their thiol ligands to facilitate release of the Au(I) atom for binding to HNC. Cd(II) and Cu(II) also inhibit HNC noncompetitively, and inhibition is also reversed by Zn(II). Collectively, these data indicate that latent HNC contains a heavy metal binding site distinct from the active site at which Au(I), Cd(II), and Cu(II) bind to cause noncompetitive inhibition. Occupancy of this site by Zn(II) is characterized by retention of activity.

Aurothioglucose↗
PubMed1998

Alveolar-interstitial pneumopathy after gold-salts compounds administration, requiring mechanical ventilation.

The pulmonary toxicity of gold salts is an uncommon cause of life-threatening respiratory failure. Currently, patients who suffer from this do not need mechanical ventilation, and the toxicity can be difficult to diagnose when it occurs in patient with an illness producing pulmonary manifestations. We report a case of severe respiratory failure due to gold salt toxicity in a patient suffering from rheumatoid arthritis requiring mechanical ventilation. At such a time, the poor respiratory function makes some diagnostic procedures harmful. The diagnosis can be made after the exclusion of other causes of rheumatoid lung when the patient's poor respiratory status precludes invasive exploration. The clinical findings, radiological features, and results of pulmonary function tests may be enough to diagnose gold-related pneumopathy. This avoids the need for bronchoscopic examination or transfer of the patient for computed tomography. Attention must be paid to this complication because the outcome and functional prognosis are better when pulmonary involvement is gold related: in our case steroid therapy was life-saving and induced complete recovery of the lung damage.

Aged↗
PubMed1993

Clinical pharmacokinetics of slow-acting antirheumatic drugs.

The pharmacokinetics of the slow acting antirheumatic drugs (SAARDs), hydroxychloroquine, chloroquine, penicillamine, the gold complexes and sulphasalazine, in humans have been studied. For all these drugs, both in controlled clinical trials and in empirical observations from rheumatological practice, delays of several months are reported before full clinical effects are achieved. Variability in response is also characteristic of these agents. Pharmacokinetic factors may partially explain these clinical observations. Delays in the achievement of steady-state concentrations or of concentrations likely to have a therapeutic benefit may occur because of slow drug accumulation. Variable concentrations may arise after standard administered doses because of interindividual pharmacokinetic variability. These factors are likely to contribute to the delay in response and the variable response, respectively. Pharmacokinetics of the antimalarials, hydroxychloroquine and chloroquine, are characterised by extensive tissue sequestration with reported volumes of distribution in the thousands of litres. Both drugs have reported elimination half-lives of greater than 1 month. A 2- to 3-fold range occurs in the fraction of an oral dose absorbed from a tablet formulation. Variable interindividual clearance is also reported. Hydroxychloroquine and chloroquine are administered as racemates. Enantioselective disposition of both compounds occurs, again with notable interindividual variability. Sulphasalazine is split in the large intestine into sulphapyridine, proposed to be the active compound in rheumatoid arthritis, and mesalazine (5-aminosalicylic acid). Sulphapyridine is metabolised partly by acetylation, the rate of which is under genetic control. A wide range of sulphapyridine steady-state concentrations are reported after standard doses of sulphasalazine. The gold complexes are administered either intramuscularly or in an oral form (auranofin). Gold is widely distributed in the body. Very long terminal elimination half-lives and slow accumulation rates are reported. Penicillamine is administered orally. Its bioavailability is variable and may decrease by as much as 70% in the presence of food, antacids and iron salts. Penicillamine forms disulphide bonds with many proteins in the blood and tissues, creating potential slow release reservoirs of the drug. Like the other SAARDs, gold complexes and penicillamine are found in a wide range of blood concentrations after administration in standard doses to different individuals. More research must be conducted into the concentration-effect relationships of the SAARDs before the pharmacokinetic characteristics of these drugs can be used effectively to optimise patient therapy.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2006

Synthesis, structural characterization, and theoretical studies of gold(I) and gold(I)-gold(III) thiolate complexes: quenching of gold(I) thiolate luminescence.

The gold(I) thiolate complexes [Au(2-SC6H4NH2)(PPh3)] (1), [PPN][Au(2-SC6H4NH2)2] (2) (PPN = PPh3=N=PPh3), and [{Au(2-SC6H4NH2)}2(mu-dppm)] (3) (dppm = PPh2CH2PPh2) have been prepared by reaction of acetylacetonato gold(I) precursors with 2-aminobenzenethiol in the appropriate molar ratio. All products are intensely photoluminescent at 77 K. The molecular structure of the dinuclear derivative 3 displays a gold-gold intramolecular contact of 3.1346(4) A. Further reaction with the organometallic gold(III) complex [Au(C6F5)3(tht)] affords dinuclear or tetranuclear mixed gold(I)-gold(III) derivatives with a thiolate bridge, namely, [(AuPPh3){Au(C6F5)3}(mu2-2-SC6H4NH2)] (4) and [(C6F5)3Au(mu2-2-SC6H4NH2)(AudppmAu)(mu2-2-SC(6)H4NH2)Au(C6F5)3] (5). X-ray diffraction studies of the latter show a shortening of the intramolecular gold(I)-gold(I) contact [2.9353(7) or 2.9332(7) A for a second independent molecule], and short gold(I)-gold(III) distances of 3.2812(7) and 3.3822(7) A [or 3.2923(7) and 3.4052(7) A] are also displayed. Despite the gold-gold interactions, the mixed derivatives are nonemissive compounds. Therefore, the complexes were studied by DFT methods. The HOMOs and LUMOs for gold(I) derivatives 1 and 3 are mainly centered on the thiolate and phosphine (or the second thiolate for complex 2), respectively, with some gold contributions, whereas the LUMO for derivative 4 is more centered on the gold(III) fragment. TD-DFT results show a good agreement with the experimental UV-vis absorption and excitation spectra. The excitations can be assigned as a S --> Au-P charge transfer with some mixture of LLCT for derivative 1, an LLCT mixed with ILCT for derivative 2, and a S --> Au...Au-P charge transfer with LLCT and MC for derivative 3. An LMCT (thiolate --> Au(III) mixed with thiolate --> Au-P) excitation was found for derivative 4. The differing nature of the excited states [participation of the gold(III) fragment and the small contribution of sulfur] is proposed to be responsible for quenching the luminescence.

Crystallography, X-Ray↗
PubMed2006

Gold(III) dithiocarbamate derivatives for the treatment of cancer: solution chemistry, DNA binding, and hemolytic properties.

Gold(III) compounds are emerging as a new class of metal complexes with outstanding cytotoxic properties and are presently being evaluated as potential antitumor agents. We report here on the solution and electrochemical properties, and the biological behavior of some gold(III) dithiocarbamate derivatives which have been recently proved to be one to 4 orders of magnitude more cytotoxic in vitro than the reference drug (cisplatin) and to be able to overcome to a large extent both intrinsic and acquired resistance to cisplatin itself. Their solution properties have been monitored in order to study their stability under physiological conditions; remarkably, they have shown to undergo complete hydrolysis within 1 h, the metal center remaining in the +3 oxidation state. Their DNA binding properties and ability in hemolyzing red blood cells have been also evaluated. These gold(III) complexes show high reactivity toward some biologically important isolated macromolecules, resulting in a dramatic inhibition of both DNA and RNA synthesis and inducing DNA lesions with a faster kinetics than cisplatin. Nevertheless, they also induce a strong and fast hemolytic effect (compared to cisplatin), suggesting that intracellular DNA might not represent their primary or exclusive biological target.

Animals↗
PubMed1994

Electron microscopy of cytochrome c oxidase crystals: labeling of subunit III with a monomaleimide undecagold cluster compound.

Two-dimensional crystals of beef heart mitochondrial cytochrome c oxidase dimers were labeled at Cys-115 of subunit III with a monomaleimide derivative of an undecagold cluster compound. The binding site of the gold cluster compound and hence the site of subunit III were identified by image processing of cryoelectron micrographs of the crystals preserved in a mixture of glucose and uranyl acetate. The shape of the cytochrome oxidase dimer can be approximated as a parallelogram which is 44 by 82 A with an included angle of 80 degrees oriented with its long dimension along the a axis of the crystal. Labeling of subunit III was confirmed by a shift in the mobility of approximately 50% of subunit III molecules upon electrophoresis in polyacrylamide gels in the presence of sodium dodecyl sulfate. Averaged images of undecagold cluster labeled crystals and of unlabeled crystals were calculated; each image represents an average of approximately 17,000 molecules of either labeled or unlabeled cytochrome oxidase. On the basis of a statistical analysis of the differences between the two images, the gold cluster binds along a line 30 degrees from the a axis and 29 A from the center of the dimer. This result is interpreted in the context of other structural studies including the site of cytochrome c binding which Frey and Murray found to be near the a axis and 18 A from the center of the dimer [Frey, T. G., & Murray, J. M. (1994) J. Mol. Biol. 237, 275-297].(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

[Molecular mechanisms of action of gold in treatment of rheumatoid arthritis--an update].

Gold was first used 90 years ago by Robert Koch for the treatment of tuberculosis based on the assumption that rheumatoid arthritis was caused by microbacteria. It soon became clear that this would not explain the action of gold in rheumatoid arthritis, and since then scientists have been struggling to elucidate the mechanisms of gold's action in the treatment of rheumatic diseases. In nearly every area of immunology inhibiting actions of gold could be documented; however, it is still unclear if there is a common denominator or if there are parallel modes of actions which are independent of each other. In any case, also based on recent studies the reactivity of gold compounds with thiol groups appears to the predominant factor. Analyzing the actions of gold in the different phases of an immune reaction suggested that gold plays an important role already in the initiation, namely the uptake and presentation of foreign antigens. Thus, gold is taken up by the macrophages and stored in the lysosomes which are called aureosomes where gold inhibits antigen processing. Especially peptide antigens, which contain sulfur such as cysteine and methionine, are important. Moreover, it could be shown that gold suppresses NF-kappa B binding activity as well as the activation of the I-kappa B-kinase. This mechanism results in a subsequently reduced production of pro-inflammatory cytokines, most notably TNF-alpha, interleukin-1 and interleukin-6. On the subsequent T-cell level, gold has been shown to induce an upregulation of IL-4 mRNA, resulting in a shift of the T-cell population to the Th2 phenotype. Moreover, the activation of T-cells is inhibited. On the effector level, gold inhibits proteolytic enzymes and can result in the destruction of synovial fibroblasts. In conclusion, gold remains one of the most fascinating antirheumatic drugs with multiple modes of actions. The future analysis of molecular mechanisms, especially with regard to signal transduction, will lead to new fundamental knowledge of gold action, possible allowing a further understanding of the pathogenesis of rheumatoid arthritis.

Antigen Presentation↗
PubMed1988

Mechanism of alterations in isolated rat liver mitochondrial function induced by gold complexes of bidentate phosphines.

Au(DPPE)+2 (bis[1,2-bis(diphenylphosphino)ethane] gold(I] is an organo-gold antineoplastic agent that has anti-tumor activity in a variety of in vitro cell lines and in vivo rodent tumor models. Preliminary studies suggested that this compound represented a novel class of inhibitors of mitochondrial function. The purpose of this study was, therefore, to determine the mechanism of mitochondrial dysfunction induced by Au(DPPE)+2. Au(DPPE)+2 induced a rapid, dose-related collapse of the inner mitochondrial membrane potential (EC50 = 28.0 microM) that was not potentiated by Ca2+ preloading. Au(DPPE)+2-induced dissipation of mitochondrial membrane potential was accompanied by an efflux of Ca2+ from mitochondria upon exposure to Au(DPPE)+2. Ca2+ efflux in these experiments was via a reversal of the Ca2+ uniporter as efflux could be inhibited with ruthenium red. Au(DPPE)+2 did not increase the permeability of mitochondria to oxalacetate, indicating that the collapse of membrane potential may not be a result of gross increased inner membrane permeability. However, Au(DPPE)+2 may mediate an increased permeability of the inner membrane to cations and protons. Au(DPPE)+2 caused passive swelling in potassium acetate buffer in the absence of valinomycin, suggesting Au(DPPE)+2 facilitated the exchange of H+ and K+. Ca2+ cycling was not extensive and did not contribute to the decrease in membrane potential. These data suggest that one possible mechanism of Au(DPPE+2-induced uncoupling of mitochondrial oxidative phosphorylation is via increased permeability of the inner mitochondrial membrane to cations. The disruption of mitochondrial function may be a key process leading to hepatocyte cell injury by this drug.

Acetates↗
PubMed1991

Auranofin inactivates phosphofructokinase in human neutrophils, leading to depletion of intracellular ATP and inhibition of superoxide generation and locomotion.

The effects of the oral gold compound auranofin (AF), at concentrations well within the therapeutic range (0.04-1.5 microM), on human neutrophil functions and energy metabolism were investigated in vitro. At the concentrations tested, this agent had minimal effects on neutrophil degranulation and phagocytosis. However, AF caused dose-related inhibition of neutrophil chemotaxis and stimulus-activated generation of superoxide, which was evident at concentrations as low as 0.04 microM. Inhibition of superoxide generation by activated neutrophils increased with the time of preincubation of the cells with AF at 37 degrees. At low concentrations of AF (less than 0.75 microM), early events (within 5 min) involved in the transduction, assembly, and activity of the neutrophil superoxide-generating enzyme NADPH oxidase appeared to be normal, but the cells were unable to sustain the level of oxygen consumption, superoxide production, and NADPH oxidase activity of the corresponding drug-free control cells. On a mechanistic level, coincubation of neutrophils with AF was associated with decreased glycolytic activity and depletion of intracellular ATP, apparently due to drug-mediated, dose-related inactivation of the glycolytic enzyme phosphofructokinase (PFK). Using purified PFK, the triethylphosphine gold (TEPG) moiety of AF, but not AF per se, caused dose-related inactivation of enzyme activity. These data indicate that the potent inhibition of neutrophil migration and reactive oxidant generation observed during treatment of neutrophils with low, therapeutically attainable concentrations of AF is related to TEPG-mediated inactivation of PFK and consequent interference with cellular energy metabolism and functions.

Adenosine Triphosphate↗
PubMed1989

The mechanism of acute cytotoxicity of triethylphosphine gold(I) complexes. III. Chlorotriethylphosphine gold(I)-induced alterations in isolated rat liver mitochondrial function.

Chlorotriethylphosphine gold(I) (TEPAu) is an organo-gold compound that has therapeutic activity in animal models of rheumatoid arthritis. Initial studies have suggested that TEPAu is a potent cytotoxic compound in vitro against a variety of cultured cell types and isolated hepatocytes. Mitochondrial dysfunction induced by this compound has been suggested as a primary biochemical alteration which may result in lethal cell injury in isolated hepatocytes. The purpose of this study was, therefore, to determine the mechanism of TEPAu-induced dysfunction of isolated rat liver mitochondria. TEPAu induced a rapid, concentration-related collapse of the mitochondrial inner membrane potential (EC50 = 24.7 +/- 2.5 microM) which was potentiated in Ca2+ loaded mitochondria (EC50 = 11.3 +/- 3.8 microM). TEPAu-induced collapse of the membrane potential was partially inhibited in the presence of ruthenium red or EGTA. TEPAu caused the rapid release of mitochondrially sequestered Ca2+ which was not inhibited by ruthenium red and, thus, was not via a reversal of the Ca2+ uniporter. TEPAu caused mitochondrial swelling, increased permeability of the inner membrane, and the oxidation/hydrolysis of endogenous mitochondrial pyridine nucleotides. Addition of exogenous ATP slightly reversed the effects of TEPAu on pyridine nucleotides. TEPAu-induced mitochondrial alterations were reversed or inhibited by exposure to the sulfhydryl reducing agent, dithiothreitol. Also, the TEPAu-induced collapse of the mitochondrial membrane potential was partially inhibited by dibucaine, a non-specific inhibitor of phospholipases. These data suggest that TEPAu-induced mitochondrial dysfunction is sulfhydryl dependent. TEPAu-induced mitochondrial dysfunction results in dissipation of the potential difference across the inner mitochondrial membrane which inhibits mitochondrial oxidative phosphorylation. The mechanism by which TEPAu induces the collapse of the membrane potential may be mediated by a sulfhydryl-dependent increase in permeability of the inner membrane to protons.

Animals↗
PubMed2002

The rheumatoid arthritis patient in the clinic: comparing more than 1,300 consecutive DMARD courses.

BACKGROUND: Therapy of rheumatoid arthritis (RA) is typically characterized by the sequential use of disease-modifying anti-rheumatic drugs (DMARDs). This study aimed to reveal treatment patterns with traditional DMARDs and their changes during the two decades before the recent introduction of new DMARDs. METHODS: A total of 593 RA patients were followed from their first presentation to our clinic throughout the course of their disease; 222 patients received their first DMARD therapy while under our care. More than 2,300 patient years of therapy were analysed for the efficacy [using C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) as surrogates] and duration of drug therapy of consecutive DMARDs. RESULTS: Before 1985, 65-90% of initial DMARDs were gold compounds, but their use decreased continuously thereafter. Antimalarial (AM) drugs were important initial DMARDs in new patients at all times, whereas sulphasalazine (SSZ) and methotrexate (MTX) gained increasing significance after 1985 (the first DMARD was MTX in up to 29% of new patients). Penicillamine (DPA), azathioprine (AZP), cyclosporin (CyA) and combination therapies were not usually employed initially, but were reserved for the later course of the disease. Gender, age and rheumatoid factor were not different between patients receiving different DMARDs. The baseline acute-phase response was higher in patients treated with MTX (mean CRP 3.5 mg/dl) than in those treated with SSZ (CRP 2.4 mg/dl; P < 0.05) or AM (CRP 2.1 mg/dl; P < 0.05), suggesting that MTX was used preferentially in patients with high disease activity. On the other hand, once AM or SSZ had been discontinued, MTX was the most common subsequent DMARD (in 31 and 56% respectively). Comparison of first DMARDs with subsequent ones revealed that first DMARDs were more effective: the acute-phase response decreased most prominently during first therapies (CRP reduction was 1.28 mg/dl during first courses and 0.35 mg/dl during fourth or later courses; P < 0.01); and retention rates were significantly longer for first compared with subsequent therapies (median of 24.5 months for first and 18.6 months for fourth or subsequent therapies; P < 0.001). CONCLUSION: MTX was the most commonly employed DMARD therapy for RA and was used increasingly as first therapy in newly diagnosed RA. Patients with high disease activity were given MTX therapy more often than other DMARDs, while those with low activity were more likely to receive SSZ or AM, and MTX on failure of these drugs. First DMARDs in new patients were retained longer than subsequent DMARDs, apparently because they are more effective.

Acute Disease↗
PubMed1987

The mechanism of acute cytotoxicity of triethylphosphine gold(I) complexes. II. Triethylphosphine gold chloride-induced alterations in mitochondrial function.

Triethylphosphine gold complexes have therapeutic activity in the treatment of rheumatoid arthritis. Many of these compounds are also highly cytotoxic in vitro to a variety of tumor and non-tumor cell lines. Triethylphosphine gold chloride (TEPAu) is highly cytotoxic to isolated rat hepatocytes at concentrations greater than 25 microM. The earliest changes that could be detected in hepatocytes included bleb formation in the plasma membrane, alterations in the morphology of mitochondria, and rapid decreases in cellular ATP and oxygen consumption. The degradation of ATP could be followed sequentially through ADP and AMP and was ultimately accounted for entirely as xanthine. The sum of adenine and xanthine-derived nucleotides remained constant throughout the experiments. TEPAu (50 microM) caused a significant decrease in the hepatocyte ATP/ADP ratio and energy charge within 5 min. The antioxidant, N,N'-diphenyl-p-phenylenediamine (DPPD), which blocked TEPAu-induced malondialdehyde formation but not cell death, also had no effect on the decreases in oxygen consumption, ATP, ATP/ADP ratio, or energy charge. In isolated rat liver mitochondria, TEPAu (1 microM) caused significant reductions in carbonyl cyanide-4-trifluoromethoxyphenylhydrazone (FCCP) (uncoupled)-stimulated respiration. TEPAu (5 microM) inhibited state 3 respiration and the respiratory control ratio without affecting state 4 respiration and caused a rapid dissipation of the mitochondrial-membrane hydrogen-ion gradient (membrane potential). Concentrations greater than 5 microM also inhibited state 4 respiration. TEPAu caused a concentration-dependent inhibition of FCCP-stimulated respiration with pyruvate/malate and succinate as substrates but had not effect on ascorbate/tetramethyl-p-phenylenediamine-supported respiration. The inhibition of state 4 respiration and FCCP-stimulated respiration by TEPAu (10 microM) could be reversed by the addition of 2 mM dithiothreitol. Dithiothreitol also partially protected cells from TEPAu-induced injury and reversed the TEPAu-induced depletion in cellular ATP. These data indicate that TEPAu may be acting functionally as a respiratory site II inhibitor, similar to antimycin. The reversal of TEPAu-induced inhibition of mitochondrial respiration and cell lethality by dithiothreitol suggests that mitochondrial thiols may be involved.

Adenosine Triphosphate↗
PubMed2000

Injectable gold for rheumatoid arthritis.

OBJECTIVES: To estimate the short-term benefit and risk of side-effects of injectable gold for rheumatoid arthritis. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Group trials register, and Medline, up to July 1997, using the search strategy developed by the Cochrane Collaboration (Dickersin 1994). The search was complemented with bibliography searching of the reference list of the trials retrieved from the electronic search. Key experts in the area were contacted for further published and unpublished articles. SELECTION CRITERIA: Randomized clinical trials (RCT) comparing injectable gold against placebo in patients with rheumatoid arthritis were included. DATA COLLECTION AND ANALYSIS: Methodological quality of the RCTs was asessed by two reviewers (MS, BS) (kappa=1.0). Rheumatoid arthritis outcome measures were extracted by two reviewers from the publications for the 6 month endpoint. Sufficient data was obtained to conduct a pooled analysis of the number of swollen joints, physician global assessment, patient global assessment and erythrocyte sedimentation rate (ESR). Results were analyzed as standardized weighted mean differences for swollen joints and global assessments and weighted mean differences for ESR. Toxicity was evaluated with pooled odds ratios for withdrawals. Heterogeneity was estimated using a chi-square test. Fixed effects models were used throughout. MAIN RESULTS: Four trials and 415 patients were included. A statistically significant benefit was observed for injectable gold when compared to placebo. The standardized weighted difference (effect size) between gold and placebo for the number of swollen joints was -0.5, translating into a percentage change of 30% in favour of gold adjusted for placebo. Statistically significant differences were also observed for ESR and patient and physician assessments. Twenty two percent of the treated patients withdrew from toxicity compared to 4% of controls (OR=3.9 - 95%Cl: 2.1 - 7.2). REVIEWER'S CONCLUSIONS: Although its use can be limited by the incidence of serious toxicity, injectable gold has an important clinically and statistically significant benefit in the short term treatment of patients with rheumatoid arthritis.

Antirheumatic Agents↗