Gold(I) ion and the phosphine ligand are necessary for the anti-Toxoplasma gondii activity of auranofin.

Auranofin, an FDA-approved drug for rheumatoid arthritis, has emerged as a promising antiparasitic medication in recent years. The gold(I) ion in auranofin is postulated to be responsible for its antiparasitic activity. Notably, aurothiomalate and aurothioglucose also contain gold(I), and, like auranofin, they were previously used to treat rheumatoid arthritis. Whether they have antiparasitic activity remains to be elucidated. Herein, we demonstrated that auranofin and similar derivatives, but not aurothiomalate and aurothioglucose, inhibited the growth of Toxoplasma gondii in vitro. We found that auranofin affected the T. gondii biological cycle (lytic cycle) by inhibiting T. gondii's invasion and triggering its egress from the host cell. However, auranofin could not prevent parasite replication once T. gondii resided within the host. Auranofin treatment induced apoptosis in T. gondii parasites, as demonstrated by its reduced size and elevated phosphatidylserine externalization (PS). Notably, the gold from auranofin enters the cytoplasm of T. gondii, as demonstrated by scanning transmission electron microscopy-energy dispersive X-ray spectroscopy (STEM-EDS) and Inductively Coupled Plasma-Mass Spectrometry (ICP-MS).IMPORTANCEToxoplasmosis, caused by Toxoplasma gondii, is a devastating disease affecting the brain and the eyes, frequently affecting immunocompromised individuals. Approximately 60 million people in the United States are already infected with T. gondii, representing a population at-risk of developing toxoplasmosis. Recent advances in treating cancer, autoimmune diseases, and organ transplants have contributed to this at-risk population's exponential growth. Paradoxically, treatments for toxoplasmosis have remained the same for more than 60 years, relying on medications well-known for their bone marrow toxicity and allergic reactions. Discovering new therapies is a priority, and repurposing FDA-approved drugs is an alternative approach to speed up drug discovery. Herein, we report the effect of auranofin, an FDA-approved drug, on the biological cycle of T. gondii and how both the phosphine ligand and the gold molecule determine the anti-parasitic activity of auranofin and other gold compounds. Our studies would contribute to the pipeline of candidate anti-T. gondii agents.

Next Generation Gold Drugs and Probes: Chemistry and Biomedical Applications.

The gold drugs, gold sodium thiomalate (Myocrisin), aurothioglucose (Solganal), and the orally administered auranofin (Ridaura), are utilized in modern medicine for the treatment of inflammatory arthritis including rheumatoid and juvenile arthritis; however, new gold agents have been slow to enter the clinic. Repurposing of auranofin in different disease indications such as cancer, parasitic, and microbial infections in the clinic has provided impetus for the development of new gold complexes for biomedical applications based on unique mechanistic insights differentiated from auranofin. Various chemical methods for the preparation of physiologically stable gold complexes and associated mechanisms have been explored in biomedicine such as therapeutics or chemical probes. In this Review, we discuss the chemistry of next generation gold drugs, which encompasses oxidation states, geometry, ligands, coordination, and organometallic compounds for infectious diseases, cancer, inflammation, and as tools for chemical biology via gold-protein interactions. We will focus on the development of gold agents in biomedicine within the past decade. The Review provides readers with an accessible overview of the utility, development, and mechanism of action of gold-based small molecules to establish context and basis for the thriving resurgence of gold in medicine.

Gold as an oral corticosteroid sparing agent in stable asthma.

BACKGROUND: Patients with chronic severe asthma are often dependent on the long term prescription of oral corticosteroids. The use of steroids is associated with serious side effects. Physicians treating such patients continue to search for alternative therapies that reduce the need for chronic dosing with oral steroids. Gold compounds are immunosuppressive agents and have benefits in the treatment of a number of inflammatory disorders. They have therefore been identified as an potentially useful agents in the treatment of chronic severe asthma both in terms of possible efficacy and as steroid sparing agents. OBJECTIVES: The objective of this review was to assess the effects of adding gold to oral steroids in the treatment of chronic steroid dependent asthmatics. SEARCH STRATEGY: The Cochrane Airways Group trials register and reference lists of identified articles were searched. SELECTION CRITERIA: Randomised trials looking at the addition of gold compared to placebo in adult steroid dependent asthmatics. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data extraction was carried out by two reviewers independently. Study authors were contacted for missing information. MAIN RESULTS: Three trials fulfilled the criteria for inclusion in the review and a total of 376 patients were recruited into these studies. Data from 311 patients could be analysed. There was a small but significant treatment effect for gold in terms of steroid dose reduction (Peto Odds Ratio 0.51, 95% confidence intervals 0.31,0.83). No meta-analysis could be done for measures of lung function although overall there were few changes suggesting a positive benefit for gold. There were trends suggestive of adverse effects but no significant changes for gold treated patients with respect to proteinuria (Peto Odds Ratio 1.4, 95% confidence intervals 0.6, 3.3) dermatitis/eczema Peto Odds Ratio 2.1, 95% confidence intervals 0.9, 4.7). REVIEWER'S CONCLUSIONS: The changes seen in these trials are small and probably of limited clinical significance. Given the side effects of gold and necessity for monitoring the use of gold as a steroid sparing agent in asthma cannot be recommended.

Aggressive treatment in early rheumatoid arthritis: a randomised controlled trial. On behalf of the Rheumatic Research Foundation Utrecht, The Netherlands.

OBJECTIVES: To compare three therapeutic strategies using slow acting antirheumatic drugs (SAARDs) in early rheumatoid arthritis (RA), for their disease modifying properties, toxicity, and lag time until treatment effect. METHODS: Patients with recent onset RA from six hospitals were randomly assigned to immediate initiation of one of three treatment strategies: (I) a "mild SAARD with a long lag time" (hydroxychloroquine, if necessary replaced by auranofin); (II) a "potent SAARD with a long lag time" (intramuscular gold, if necessary replaced by D-penicillamine); (III) a "potent SAARD with a short lag time" (methotrexate, if necessary replaced by sulfasalazine). Comparisons included two years of follow up. RESULTS: All SAARD strategies reduced mean disease activity. A greater percentage of patients improved clinically with strategies II and III than with strategy I: percentages of patients improved on joint score with strategies II and III (79% and 82%, respectively), which was statistically different from strategy I (66%). The same was true for remission percentages: 31% and 24% v 16%, respectively). Longitudinal analysis showed significantly less disability with strategy III, and a lower erythrocyte sedimentation rate with strategy II than with strategy I. In addition, radiological damage after one and two years, was significantly lower in strategies II and III (at two years median scores were 11 and 10 v 14 in strategy I, p<0.05). Toxicity was increased in strategy II compared with the other strategies. CONCLUSION: Strategy III, comprising methotrexate or sulfasalazine, produced the best results weighing effectiveness and toxicity. Strategy I (hydroxychloroquine or auranofin) was slightly less effective, and strategy II (intramuscular gold or D-penicillamine) was associated with increased toxicity.

Anti-Ro (SSA) antibodies in rheumatoid arthritis patients with gold-induced side effects.

The purpose of our study was to investigate the significance of the presence of anti-Ro antibodies found by us in an earlier study of rheumatoid arthritis (RA) patients with gold-induced side effects. Sera of 29 anti-Ro (SSA) positive RA patients who had gold-induced side effects were studied. All sera were examined by Western blot using recombinant antigens, encoding the Ro 60 kD and the La proteins. HLA typing was done in all patients. Thirteen patients reacted only with the Ro 52 kD antigen and all had severe skin eruptions caused by gold therapy. Another ten patients who reacted only with the Ro 60 kD antigen had other side effects to gold (six had proteinuria and four leucopenia). Six patients who reacted to all three antigens (Ro 52 kD, Ro 60 kD and La) had secondary Sjögren's syndrome. No significant statistical differences were noted in the incidence of HLA-DR3 between the subgroups of patients. Our data indicated that antibodies to the Ro 52 kD antigen are associated with skin eruptions in RA patients treated with gold.

Use of corticosteroids and aurothioglucose in a pygmy goat with pemphigus foliaceus.

Pemphigus foliaceus was diagnosed in a 20-month-old female pygmy goat. The goat had a 3-month history of chronic exfoliative dermatitis and was examined after developing alopecia and severe, asymmetric, diffuse flakes of dry, nonadherent skin scales. Pemphigus foliaceus was diagnosed on the basis of dermatohistologic findings and was confirmed by analysis of results of direct immunofluorescence testing of perilesional specimens obtained by use of a punch biopsy. The goat was successfully treated with prednisolone (immunosuppressive induction dosage; 1 mg/kg of body weight, IM, q 12 h). Remission was achieved in 1 week and was maintained by use of prednisolone (immunosuppressive maintenance dosage; 1 mg/kg, IM, q 48 h). Treatment with aurothioglucose (1 mg/kg, IM, q 7 d) that was initiated during administration of prednisolone and was continued after discontinuation of corticosteroid administration failed to prevent redevelopment of pemphigus foliaceus.

Oral steroids as bridge therapy in rheumatoid arthritis patients starting with parenteral gold. A randomized double-blind placebo-controlled trial.

The efficacy of oral prednisone as bridge therapy in rheumatoid arthritis (RA) was studied. Forty patients starting aurothioglucose were randomized to receive either prednisone or placebo for 18 weeks. The dose was 10 mg/day in the first 12 weeks, 7.5 mg/day in weeks 13 and 14, 5 mg/day in weeks 15 and 16, and 2.5 mg/day in weeks 17 and 18. Patients were followed for 44 weeks. We found that disease activity was significantly lower in the prednisone group as early as week 1 and continued up to week 12. Response to prednisone was noticed in 60% of the patients. After tapering prednisone, a rebound deterioration was noticed at weeks 20 and 24 in 58% of the responders. No significant differences in X-ray progression were found between the two groups. We concluded that oral prednisone (10 mg/day) significantly reduces short-term disease activity in 60% of patients with active RA. The rebound deterioration after tapering the dose means that bridge therapy with prednisone using this dose-reduction scheme is not recommended.

Prospective studies of thyroid function in patients receiving gold therapy.

Gold inhibits the Type I deiodinase that provides the bulk of circulating T3 in humans. We prospectively studied thyroid function in patients receiving increasing parenteral cumulative gold doses. Eight consecutive euthyroid patients with rheumatoid or psoriatic arthritis who were initiating intramuscular gold therapy were enrolled. Serum thyroid hormone levels (total T4, T3, and rT3) and TSH were measured for each subject at various levels during gold therapy. For analysis, the free T4 and free T3 indices, TSH concentrations, and T4/T3 ratios were correlated with cumulative gold dose. Neither individual nor pooled linear regressions showed a significant correlation between cumulative gold dose and any of the thyroid function parameters. Thyroid function is not affected in patients receiving up to 1500 mg of gold compounds. The most likely explanation for this is that gold principally accumulates in the Kupffer cells and renal cortex and these cells do not express Type I deiodinase.

Anti-inflammatory properties of copper, gold and silver, individually and as mixtures.

It has been previously demonstrated that the mixture of Cu, Au and Ag impaired significantly the clinical and biochemical disorders induced by adjuvant arthritis in the rat. The efficiency of this mixture and of each component was tested on the same animal model. Treated rats were injected daily with either 22.8 micrograms of copper gluconate, 0.2 micrograms of gold thioglucose, 6.8 micrograms of silver proteinate or the blended solution over a period of 29 d. The treatment with the one component solutions was found to have a little or no effect on the plasma levels of fibrinogen, haptoglobin, ceruloplasmin, prostaglandin E2, thromboxane B2, total proteins, Zn, Cu, Mn, Se, Co and Ni, and no significant decrease was observed in the paw oedema resulting from the Freund's adjuvant injection. The treatment with the mixture had a significant preventive effect. Therefore it seems that the administration of low doses of each of the three trace elements have no anti-rheumatic property in the rat. The results indicate an enhanced effect of the metal mixture in the model studied.

Mucocutaneous reactions to gold: a prospective study of 74 patients with rheumatoid arthritis.

OBJECTIVE: To describe causality, morphology, course, and risk factors of mucocutaneous reactions to gold. METHODS: A prospective study of 74 patients with rheumatoid arthritis starting with gold thioglucose. RESULTS: Thirty-nine patients experienced an episode of gold dermatitis. Sixteen patients continued gold treatment. The estimated treatment withdrawal at 1 year was 26%. The clinical picture was variable and nonspecific. Gold dermatitis was associated with HLA-B35 and disease duration. CONCLUSION: Mucocutaneous reactions to gold are nonspecific, therefore a causality assessment is necessary. Incidence is high, but treatment can often be continued with dose reduction and local steroids. The predictive value of risk factors is low.

Adverse immune reactions to gold in rheumatoid arthritis: lack of skin reactivity.

Adverse immune reactions develop in up to 30% of patients treated with gold compounds. However, sensitization to gold(I) drugs is rarely demonstrated by in vivo or in vitro testing. Recent data from a mouse model provides evidence that gold(I) is oxidized to gold(III) before T cells are sensitized. To study the diagnostic value of skin tests, patch testing with various gold compounds - including gold(I) and gold(III) - was performed in 50 patients with rheumatoid arthritis treated with gold(I) drugs. Positive patch test reactions to either gold(I) or gold(III) compounds were not detected. In contrast, the lymphocyte transformation test (LTT) revealed a gold(III)-induced response in one of the 7 patients being tested. We conclude that patch testing fails to indicate T cell sensitization to gold(I) drugs in rheumatoid arthritis patients. The in vitro response to gold(III) obtained by LTT supports the hypothesis that biooxidation of gold(I) compounds may play a crucial role for sensitization.

Drug treatment of arthritis. Update on conventional and less conventional methods.

Nonsteroidal anti-inflammatory drugs comprise an important class of medications that reduce the signs and symptoms of osteoarthritis and rheumatoid arthritis. They bring relief to millions of people but do not eliminate underlying disease. Disease-modifying antirheumatic drugs also bring relief, but these drugs are often ineffective and not well tolerated. Failure to provide long-term benefits combined with the high toxicity of most of the disease-modifying agents has prompted a search for more effective treatments. New methods using modern technologies have generated much enthusiasm and hold promise for the future. In the meantime, administration of nonsteroidal anti-inflammatory drugs and judicious use of disease-modifying agents remain the cornerstone of therapy for arthritis.

Gold-induced colitis: a case report and review of the literature.

A case of severe colitis requiring subtotal colectomy following administration of 35 mg Solganal b for intractable arthritis is described. Abdominal pain and watery diarrhea developed six weeks after the last dose of gold. Colonoscopy revealed mucosal edema and ulceration of the entire colon. Supportive measures failed and the patient required subtotal colectomy. Review of the literature revealed 29 cases, ranging in severity from limited ileal involvement to fulminant panenteritis. Most of the patients responded to intravenous fluids, steroids, and antibiotics, but four required surgery. The case described is notable for the delay in appearance of abdominal symptoms following the cessation of gold therapy. The mechanism of injury is unknown. Abdominal complaints in a patient who has received gold therapy, especially parenteral, merit strict attention, even if occurring several weeks after the final dose, and the diagnosis of gold colitis should be entertained.

Decreased level of antibodies against Helicobacter pylori in patients with rheumatoid arthritis receiving intramuscular gold.

BACKGROUND: Sodium aurothiomalate has been reported to have in vitro activity against Helicobacter pylori. Intramuscular gold, as given to patients with rheumatoid arthritis (RA), may therefore influence the colonisation of the gastric mucosa with H pylori. METHODS: Two groups were compared. One group of 42 patients was treated with intramuscular gold; the other group of 58 patients was treated with antimalarial drugs. Antibodies to H pylori (IgA and IgG) were assessed by an enzyme linked immunosorbent assay (ELISA) and total IgA and IgG were measured by nephelometry. RESULTS: IgA and IgG antibody titres against H pylori and total IgA and IgG levels were lower in the patients treated with gold than in the group treated with antimalarial drugs. The ratio of IgA antibodies to H pylori to total IgA antibodies and the ratio of IgG antibodies to H pylori to total IgG antibodies were lower in the group treated with gold. The percentage of seropositivity to H pylori was significantly lower in the group treated with gold than in the group treated with antimalarial drugs for the two IgA antibodies (35 and 55% respectively) and IgG antibodies to H pylori (40 and 65% respectively). CONCLUSIONS: Although this study cannot completely exclude the possibility that a suppressive effect of intramuscular gold on total immunoglobulin production plays a part in the decrease in the titres of IgA antibodies to H pylori and IgG antibodies to H pylori, the lower ratios of antibodies to H pylori to total immunoglobulin antibodies and the lower percentages of seropositivity to H pylori in the group treated with gold suggests that treatment with intramuscular gold decreases H pylori colonisation.

Plasma cell stomatitis-pharyngitis in cats: 40 cases (1973-1991).

Clinical signs, laboratory findings, and treatment results of 40 cats with the histologic diagnosis of plasma cell stomatitis-pharyngitis are discussed. Median age was 7.1 years, with no discernable sex predilection. Anorexia and difficulty prehending food were the most common clinical signs. Hyperproteinemia with associated hyperglobulinemia was the most common laboratory finding. Of various treatments, administration of corticosteroids or injectable gold (aurothioglucose) proved most effective in controlling the clinical signs.

Long-term second-line treatment: a prospective drug survival study.

The long-term use of second-line antirheumatic drugs was prospectively studied in a consecutive sample of 245 patients with recently diagnosed rheumatoid arthritis. A survival analysis was done in which treatment termination due to side-effects and to insufficient therapeutic effect were used as index causes. Cumulative drug 'survival' of aurothioglucose with treatment termination due to toxicity was significantly less compared with hydroxychloroquine. With regard to lack of efficacy as index cause, the administration time of hydroxychloroquine was significantly less than that of either aurothioglucose or sulphasalazine. Treatment termination due to lack of efficacy or combined insufficient therapeutic response and toxicity proved to be influenced by the initial disease activity and by the rank order of prescription.

Pharmacology of antiarthritic drugs.

The clinical use of corticosteroids and second-line antirheumatic drugs provides relief in many patients but is associated with short-term and long-term toxicity. The beneficial effects are evident but are not well understood, particularly for the second-line agents. Rheumatoid arthritis is associated with abnormalities in macrophage, lymphocyte, and fibroblast functions. Corticosteroids and second-line agents appear to alter many of these responses (Table 2). Effects on macrophage and other antigen processing and phagocytic cells are common, but T- and B-lymphocytes also may be affected. Some of these agents have direct anti-inflammatory properties by inhibiting prostaglandin or leukotriene synthesis. A few are able to inhibit fibroblast proliferation and secretion of inflammatory mediators. Many other activities are possible. Understanding pharmacokinetics also should assist in determining dosing, possible consequences of other disorders, and predicting duration of acute effects. A better understanding of the disease process in rheumatoid arthritis and other disorders treated with these agents will lead to the better therapeutic approaches and, it is hoped, the discovery of more specific and less toxic agents.