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PubMed1995

Disease-modifying antirheumatic drugs. Potential effects in older patients.

Disease-modifying antirheumatic drugs (DMARDs) are frequently used in rheumatoid arthritis. A number of physiological changes occur in the elderly which may modify the use of these medications. The most commonly used DMARDs are antimalarial drugs (particularly hydroxychloroquine), sulfasalazine and methotrexate. The principal mechanism of action of the antimalarials relates to the fact that they change intracellular pH, which downregulates numerous immune functions. Hydroxychloroquine is metabolised to 3 metabolites and has a very low clearance. It is moderately effective in dosages up to 6.4 mg/kg/day. While it is not the most effective of the DMARDs, it is the least toxic. Sulfasalazine is a prodrug which is enzymatically split in the bowel to form sulfapyridine (the principal active metabolite) and 5-aminosalicylic acid. The metabolism of sulfasalazine is complex and, to some extent, genetically determined. The mechanism of action of the drug is not well understood, but involves decreased production of cytokines and decreased proliferative response of lymphocytes. It may slow the rate of bony damage associated with rheumatoid arthritis. Nearly 50% of the patients who are prescribed sulfasalazine continue to receive the drug for up to 4 years. Sulfasalazine is not as well tolerated as hydroxychloroquine. Gastrointestinal toxicity, in particular, seems to be a problem in elderly patients taking this medication. Methotrexate is presently the most popular of the DMARDs for the treatment of rheumatoid arthritis. Methotrexate inhibits dihydrofolate reductase and adenosine release and has a secondary effect on cytokines and polymorphonuclear chemotaxis. It is highly metabolised within cells and remains there for prolonged periods. Up to 70% of patients who are prescribed methotrexate continue treatment for 5 years. Methotrexate treatment is associated with gastrointestinal, hepatic, cutaneous and, possibly, pulmonary adverse effects. The use of azathioprine, penicillamine and gold compounds is briefly reviewed in this article. Elderly patients have an increased incidence of rashes when using penicillamine, relative to young patients. There are no age-related differences in the efficacy and tolerability of azathioprine or gold therapy. The poor absorption and renal toxicity associated with cyclosporin, the new 'salvage' therapy in rheumatoid arthritis, make it generally unsuitable for use in the elderly, except under specialists' supervision.

Aged↗
PubMed1981

Mechanisms of action of gold.

Since the successful introduction of injectable gold compounds for the treatment of rheumatoid arthritis over 50 years ago, numerous studies on the possible mechanism of action have been performed. This heavy metal has been show to possess a bewildering array of biological effects. Studies using gold performed both in vitro and in vivo can be grouped into anti-microbial, anti-immunologic, anti-inflammatory, anti-enzymatic and other effects. In this survey, we have analyzed these multiple approaches to the study of the mechanism of action of injectable gold preparations and apply the findings to rheumatoid arthritis.

Animals↗
PubMed2005

Ligand effects on ESR and optical properties of gold atoms in gamma irradiated organic solid solutions at 77 K.

Ligand effects on ESR and optical properties of Au0 atoms produced at 77 K in gamma irradiated solid solutions of AuCl/MTHF and AuCl/EtOH with and without HCl were investigated. Four groups of ESR lines were observed at 73 K more clearly around the magnetic fields at about 250, 280, 340, and 400 mT for both gamma irradiated MTHF and EtOH solid solutions with HCl than those without HCl. The values of a and g(J) calculated by Breit-Rabi analysis showed a remarkable dependence on the solvent polarity. It was confirmed that the signals were the hyperfine quartet corresponding to the transitions between the Zeeman levels of Au0 atoms with nuclear spin of 3/2 in the ground state, 2S(1/2). It was also confirmed that Au0 atoms produced after gamma irradiation were located in the nuclear environment of isotropic interaction with surrounding ligand molecules. Delocalization of the unpaired spin density of Au0 onto ligands is found to be as large as one in the case of Cu0 atoms. Our previous hypothesis of the occurrence of configuration mixing of d valence orbital into the wave function of the atom in its 2S(1/2) was strongly supported. The dependence of the ESR, optical absorption, and the steady-state emission and excitation characteristics on solvent polarity was cleared in this study. We observed two kinds of emissions i.e., a band at 385 nm and a set of emission bands at 456, 482, 484, and 520 nm. These correspond to two bands out of the six kinds of emissions observed previously. The bands were attributed to exciplex (Au0 x Ln...Au+)* and the excited Au0 atoms trapped in a large cavity, respectively. The negative counterion of Au+ of the gold compound plays an important role for the formation of the exciplexes.

Electron Spin Resonance Spectroscopy↗
PubMed1991

Toxicity profiles of disease modifying antirheumatic drugs in rheumatoid arthritis.

The toxicity profiles of 7 disease modifying antirheumatic drugs (DMARD) (hydroxychloroquine, intramuscular (im) gold, D-penicillamine, oral gold, methotrexate (MTX), azathioprine and cyclophosphamide) were evaluated in 2,479 patients with rheumatoid arthritis consecutively enrolled at 5 centers in the Arthritis, Rheumatism and Aging Medical Information System (ARAMIS) program. Incidence rates for side effects are reported as events/1000 patient-years. Our descriptive study revealed an individual profile of prevalent toxicities for each drug. Oral gold was characterized by substantial lower gastrointestinal (GI) toxicity (diarrhea 391 events/1000 patient-years, loose bowel movement 148, lower abdominal pain 76), MTX by hepatotoxicity (47) while D-penicillamine had the only clinically significant incidence of altered taste (40). MTX users reported the most mucosal ulcers (87), followed by oral gold (76), im gold (55) and D-penicillamine (38). Rash was frequently seen with gold compounds and D-penicillamine, while upper GI toxicity was common with immunosuppressive agents. Cyclophosphamide had 48% discontinuations within 6 months. MTX had the lowest discontinuation rate in the first 6 months, but then showed little difference from im gold. A preliminary similarity index was developed to compare the toxicity profiles of various DMARD. Close similarities were found between toxicity profiles of im gold and D-penicillamine, and between azathioprine and MTX. Oral gold had a unique toxicity pattern. Knowledge of these different toxicity patterns can enable more appropriate selection of agents for particular patients.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1984

Auranofin: a unique oral chrysotherapeutic agent.

Auranofin is a chemically unique gold coordination complex with demonstrated antiarthritic properties on oral administration. Its pharmacokinetic and immunologic profiles are distinct from injectable gold compounds. When auranofin is added to a regimen of salicylates and/or a nonsteroidal antiinflammatory drug for the treatment of RA, significant additional therapeutic benefit is observed. Published studies indicate that auranofin given 6 mg per day approaches the efficacy of parenteral gold salts in the treatment of rheumatoid disease. Noticeable improvement in clinical and laboratory parameters of disease activity has been observed by the third month of auranofin therapy. Further benefit occurs in some patients during the remainder of the first year of treatment. In the more than 3,000 patients treated with auranofin, the most frequently reported side effects were gastrointestinal (mainly diarrhea) and mucocutaneous. Most side effects were mild in nature and the withdrawal rate due to all adverse reactions averaged 11%. Auranofin differs from injectable gold by producing more gastrointestinal but fewer mucocutaneous reactions. The severity of these reactions is less with auranofin and causes fewer withdrawals from therapy.

Anti-Inflammatory Agents↗
PubMed1980

Effect of auranofin on antibody-dependent cellular cytotoxicity (ADCC) mediated by rat peripheral blood polymorphonuclear leukocytes and mononuclear cells.

Auranofin and other clinically used gold compounds were evaluated in vitro for effects on antibody-dependent cellular cytotoxicity (ADCC) of L929 fibroblast target cells mediated by adjuvant rat peripheral blood PMNs or mononuclear cells. Auranofin (10 microM) was found to be a potent inhibitor of PMNADCC. In contrast, gold sodium thiomalate (10-100 microM), gold thioglucose (10-1000 microM), and nongold substructures of auranofin (10 microM) were not inhibitory.. In continuous culture, gold sodium thiomalate and relatively low concentrations of auranofin (smaller than or equal to microM) significantly enhanced PMNADCC. Results of pretreatment studies indicate that auranofin's inhibitory activity of PMNADCC is caused by a noncytotoxic effect on PMN function which is not associated with alteration of PMN-target cell contact. In contrast to its inhibitory activity on PMNADCC, auranofin pretreatment of mononuclear cells resulted in enhanced target cell destruction which appeared to correlate with increased mononuclear cell-target cell contact.

Animals↗
PubMed1999

Trace elements in the treatment of rheumatic conditions.

The role of trace metallic elements (copper, selenium, zinc, gold) in chronic inflammatory states is of great interest because many of them are co-factors in metabolic processes involving articular tissues and immune system function. Deficiencies of several of these have been documented in patients with rheumatoid arthritis. Other than for the clinically approved gold compounds, there exists only inconsistent evidence for a therapeutic role of trace metallic elements in the management of rheumatoid arthritis.

Complementary Therapies↗
PubMed1982

Auranofin therapy in rheumatoid arthritis.

Gold is well established as an agent to suppress progressive rheumatoid arthritis. Until recently, gold could only be given parenterally. An orally absorbable gold compound, auranofin, has been undergoing clinical trials in the last 6 years. Auranofin has some effects on the immunologic system, demonstrated in vitro, that differ from its parenteral counterpart, GST. Auranofin appears to have clinical effectiveness in rheumatoid arthritis that approximates that of parenteral gold. Although gastrointestinal toxicity is more frequent with auranofin, renal toxicity is distinctly less frequent than with parenteral gold. There is preliminary evidence that auranofin may have a disease-altering capability, as measured by serial radiographs, similar to that of parenteral gold.

Administration, Oral↗
PubMed1978

Rheumatoid arthritis.

Management should help relieve symptoms, increase or maintain function, produce few side effects and keep the cost to a minimum. Aspirin remains the first-line drug; other nonsteroidal anti-inflammatory drugs may be useful when aspirin cannot be tolerated. Symptoms and signs of rheumatoid disease may be suppressed by corticosteroids, but only gold compounds, penicillamine and cytotoxic therapy have been shown to decrease disease activity and lessen permanent joint damage.

Adrenal Cortex Hormones↗
PubMed1986

Effects of aurothioglucose and auranofin on radiographic progression in rheumatoid arthritis.

Radiographic films of 40 patients participating in a single centre patient blind study of auranofin versus aurothioglucose were evaluated in a random order by one reader. The two treatment groups were comparable with respect to number of erosions and total radiographic score at the start of the study. Only in the auranofin-treated patients was a statistically significant increase in the mean number of new erosions (p less than 0.001 at 6 months and p less than 0.01 at 12 months treatment, paired t-test) as well as in the total radiographic score (p less than 0.01 at 6 and 12 months treatment, paired t-test) observed. Results of this study confirm that parenteral gold compounds do retard radiographic progression of joint destruction in the treatment of rheumatoid arthritis. The effects on radiographic progression shown in this study are in agreement with other reports which, based on clinical and biochemical parameters, have shown that auranofin is somewhat less effective than the injectible gold salts.

Adult↗
PubMed1997

[A refractory case of adult-onset Still's disease].

We report here a case of adult-onset Still's disease (AOSD), who finally responded to a combination of cyclophosphamide (CPA) and gold sodium thiomalate (GST) after two years of active disease. A 23-year-old man having continuous high fever with skin rash, polyarthralgia and increased serum ferritin, was diagnosed as AOSD, and oral corticosteroid was initially effective. His symptoms recurred one year later without clinical improvement to increased dosage of steroid. He was admitted to our hospital with pericarditis and pleural effusion but did not respond to either intravenous (i.v.) pulse steroid therapy, methotrexate (MTX) or high dose i.v. gamma-globulin. He was partly responsive to monthly i.v. injection of CPA, but clinical symptoms did not completely subside and hyperferritinemia persisted. GST, initiated in combination with CPA, however, was successful to induce complete remission. MTX has recently been reported to be efficacious to steroid-resistant AOSD, but CPA and gold compounds might be useful to refractory case of AOSD.

Adult↗
PubMed1988

Rabbit articular chondrocytes: an in vitro model for studying the effect of sodium aurothiopropanol sulfonate on proliferation kinetics, type II collagen phenotype and mitochondrial activity.

Despite the benefits of chrysotherapy the responsible mechanism of action of gold compounds remains unclear. At a concentration of 5 x 10(-4) M, sodium aurothiopropanol sulfonate (SAS) modified the in vitro proliferation kinetics of articular chondrocytes by reducing growth, viability and plating efficiency. Flow cytometry analysis, using propidium iodide DNA staining, revealed slight but significant cell arrest in G2+M which, in fact, represents an increase in the proportion of binucleate cells. SAS did not induce any variations in chondrocyte phenotype stability as far as the biosynthesis of type II collagen was concerned, and no appreciable changes in overall mitochondrial activity reflected by rhodamine 123 incorporation.

Animals↗
PubMed1975

Effect of gold on the immune response of mice.

Separate concurrent injection of organic gold compounds and antigen into mice resulted in immunoenhancement that could be measured by direct and indirect plaque-forming cells, rosette-forming cells, and serum antibody assays. Kinetics of the immune response showed variable effects through day 9 of the experiment. Studies with British anti-lewisite, a gold antagonist, showed that the gold must stay in the system 1 day to obtain immunoenhancement.

Animals↗
PubMed1983

Biologic actions and pharmacokinetic studies of auranofin.

The preclinical profiles of auranofin (Ridaura), an oral chrysotherapeutic agent, parenteral gold sodium thiomalate, gold thioglucose, and their respective ligands were compared. Auranofin was more effective than gold sodium thiomalate in suppressing inflammation and stimulating cell-mediated immunity. In contrast to gold sodium thiomalate and gold thioglucose, auranofin inhibited cellular release of lysosomal enzymes, antibody-dependent cellular cytotoxicity, production of antibodies in adjuvant arthritic rats, and antibodies involved in cytotoxicity reactions. The respective ligands were without significant biologic activity. In rats, a higher fraction of gold was associated with blood cells after auranofin administration than after gold sodium thiomalate. The absorption, distribution, metabolism, and excretion of auranofin are uniquely different from other gold compounds.

Animals↗
PubMed1979

Effects of sodium aurothiomalate on hyaluronic acid synthesis in normal and rheumatoid synovial fibroblast cultures.

In studies with normal and rheumatoid synovial fibroblast cultures the effects of sodium aurothiomalate on the quantity and quality of hyaluronic acid were tested. This gold compound produced one clear effect: the molecular weight of hyaluronate produced by rheumatoid fibroblasts was increased (shifted towards normal) whereas the effects on the amounts of hyaluronic acid synthesized were small in both rheumatoid and control cultures. The importance of this finding in relation to the known beneficial effects of gold preparations in clinical medicine is discussed.

Adolescent↗
PubMed1988

Panhypogammaglobulinaemia caused by gold therapy.

Gold compounds have been successfully used for over 50 years in the treatment of rheumatoid arthritis, but their mechanism of action is unknown. The main disadvantage is the frequent occurrence of side effects which often necessitate discontinuation of therapy. Recently, there have been reports of reduction in immunoglobulin levels in patients on gold treatment; we report a further case of hypoglobulinaemia associated with gold therapy and recommend that immunoglobulins be monitored prior to and during treatment.

Agammaglobulinemia↗
PubMed1991

Action of gold sodium thiomalate on experimental thrombosis in vivo.

In order to study the effect of gold compounds on the action of thrombin in vivo, experiments were performed to measure platelet survival and the weight of thrombus formation in experimental models of intra-aortic thrombosis by two indwelling aortic catheter methods. We have called these the long and short catheter methods. Platelet survival was reduced in all gold-treated and control animals which had indwelling aortic catheters. In the long catheter model, New Zealand White male rabbits were treated with one of the following: gold sodium thiomalate, sterile water, gold thioglucose, gold sodium thiosulfate, disodium thiomalate. Gold sodium thiomalate-treated rabbits had a reduced weight of experimentally induced intra-aortic thrombi compared with animals treated with sterile water or equimolar concentrations of gold thioglucose, gold sodium thiosulfate, or disodium thiomalate. This reduction in thrombus weight in the animals treated with gold sodium thiomalate was not reflected by changes in platelet survival or fibrinolysis. The serum gold levels achieved in these in vivo experiments was in the range of 5.0 X 10(-5) to 1.0 X 10(-4) M. These values are comparable to levels which can be achieved in human subjects immediately after a gold injection. In the short catheter model, New Zealand White male rabbits were treated with either gold sodium thiomalate, gold thioglucose, disodium thiomalate, or auranofin. Controls were given either water or 0.05% chlorocresol. Water-treated and gold sodium thiomalate-treated animals were also given 51Cr-labeled platelets and 125I-fibrinogen before insertion of the catheter.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Failure of sodium aurothiomalate and triethyl phosphine gold to cause renal tubular injury in rheumatoid arthritis: implications for the aetiology of gold-related nephropathy.

The urinary excretion of two proteins, B-2-microglobulin (beta 2M) and N-acetyl-B-D-glucosaminidase (NAG) was measured in 25 patients with rheumatoid arthritis (RA) on nonsteroidal anti-inflammatory drugs (NSAID). Although beta 2M excretion was normal NAG excretion was raised. As NAG excretion by a group of osteoarthritis patients receiving similar doses of NSAIDs was normal, it is concluded that rheumatoid disease per se may be associated with mild renal tubular dysfunction. Twelve of the above 25 patients were then given oral triethylphosphine-gold (auranofin) 6 mg daily and urinary beta 2M and NAG were measured after 6 months' treatment. Urinary excretion of beta 2M and NAG was also measured in 13 patients with RA established on intramuscular sodium aurothiomalate (MGST) and NSAIDs. Neither auranofin nor myocrisin were found to further significantly increase beta 2M and NAG excretion. These results suggest that gold compounds are not toxic to renal tubular epithelium.

Acetylglucosaminidase↗