Effects of aurothiomalate and gold(III) complexes on spontaneous motility of isolated human oviduct.

Organic gold complexes have different biological activity, depending on their potential for interactions with key functional molecules.The aim of this study was to investigate potential of several newly synthesized organic gold complexes to influence spontaneous motility of the Fallopian tubes.The effects of [Au(bipy)Cl(2)](+) (dichloride(2,2'-bipyridyl)aurate(III)-ion), aurothiomalate, [Au(DMSO)(2)Cl(2)]Cl and DMSO on spontaneous motility of Fallopian tubes were tested on the isolated tube segments in vitro. Aurothiomalate (from 2.9 × 10(-9) to 4.9 × 10(-4) M/l), [Au(bipy)Cl(2)]Cl (from 3.3 × 10(-9) to 4.2 × 10(-5) M/l) and DMSO (from 1.9 × 10(-8) to 1.0 × 10(-5) M/l) did not affect spontaneous contractions of the isolated Fallopian tube ampulla, while [Au(DMSO)(2)Cl(2)]Cl (from 2.9 × 10(-9) to 4.2 × 10(-5) M/l) showed concentration-dependent increase (stimulation) of spontaneous contractions of the isolated Fallopian tube isthmus, and remained without effect on the isolated ampulla.The drugs designed as organic gold complexes with weaker bonds between the gold itself and organic part of a molecule could adversely affect motility of the Fallopian tubes, and theoretically fertility of women taking such drugs in their reproductive age.

Gold sodium thiomalate for the treatment of rheumatoid arthritis in a patient with hepatitis B.

OBJECTIVE: To describe a case of gold sodium thiomalate use for the treatment of rheumatoid arthritis (RA) in a patient with hepatitis B. CASE SUMMARY: A 53-year-old Korean American woman with mild RA and chronic hepatitis B infection was treated for worsening RA symptoms with subcutaneous injections of gold sodium thiomalate for 21 months, with the dosage decreased from the initial 40 mg per week to 40 mg every 3 weeks after 51 weeks of successful treatment. She had undergone treatment for hepatitis B in the past with lamivudine; however, she had not received that medication for at least 1 year prior to initiating treatment with gold sodium thiomalate injections. During the treatment period she achieved remission of RA without a significant elevation of her liver enzyme levels or reactivation of hepatitis B. DISCUSSION: Two main factors influence drug product selection when considering the subset of RA patients with chronic hepatitis B infection: severity of liver function compromise and treatment status of chronic hepatitis B. Our patient did not demonstrate significant liver function compromise, but was not receiving viral suppressive treatment for hepatitis B; therefore, the use of many first-line nonbiologic disease-modifying antirheumatic drugs (DMARDs) was contra-indicated based on current guideline recommendations. Additionally, because the patient had refused viral suppressive therapy, there was great concern with the use of biological DMARDs and potential reactivation of hepatitis B. In the past, gold salts were the standard of care in treating RA until the development of the newer agents and there was some evidence that gold sodium thiomalate could be used with minimal risk of hepatotoxicity. CONCLUSIONS: Gold sodium thiomalate proved to be a safe and effective treatment option in a patient with RA and hepatitis B.

Promiscuous interaction between gold-specific T cells and APCs in gold allergy.

Gold compounds clinically used as immunomodulators have high potential to evoke hypersensitivity reactions as an adverse effect. To explore the mechanism of gold allergy, we immunologically characterized T cells infiltrating skin rashes and generated 44 gold-specific T cell clones and lines from a rheumatoid arthritis patient who developed skin rashes and systemic symptoms after gold treatment. CD4(+) and CD8(+) cells predominantly infiltrating the skin rashes and some of the T cell clones and lines shared common Vbetas. These cells exhibited Th0-like, Th2-like, and Tc1-like cytokine profiles, and showed chemotactic activities for thymus and activation-regulated chemokine and IFN-gamma-inducible protein-10 corresponding to the cytokine profiles. T cell recognition of gold consisted of MHC-restricted and MHC-independent pathways. Blocking studies with anti-MHC Abs indicated that the groove of MHC in APCs, where Ags should ordinarily be settled, did not serve as a conjugating site of gold for these T cells in certain cases. These observations raise the possibility that gold-specific CD4(+) and CD8(+) T cells and APCs promiscuously interact under stimulation with gold, resulting in various clinical manifestations in gold allergy.

Corneal chrysiasis: in vivo confocal microscopy analysis.

PURPOSE: To describe the in vivo confocal microscopy corneal findings in a patient treated with gold sodium thiomalate. METHODS: A woman with rheumatoid arthritis who had been treated with gold sodium thiomalate for 32 years came to our center for an ophthalmologic examination about 5 years ago. Besides visual acuity, the examination included slit-lamp biomicroscopy, intraocular pressure, and funduscopy. Confocal microscopy was performed using Confoscan 4 (Nidek Technologies, Padova, Italy) with a 40x lens. RESULTS: Every layer of the cornea is affected by gold deposits with high reflectivity, especially in the anterior stroma, where they have a larger dimension. CONCLUSIONS: Corneal chrysiasis can be evaluated by confocal microscopy, giving information on corneal metabolism and physiology.

Investigation of contact allergy to dental metals in 206 patients.

BACKGROUND: Contact allergy to dental materials is poorly understood; clinical manifestations are heterogeneous. OBJECTIVE: To analyse positive patch test reactions to metals (as their alloys or salts) used in dentistry together with clinical symptoms and possible relevance to dental fillings. METHODS: We retrospectively analysed 206 patients who underwent patch testing with metals used in dentistry because of suspected contact allergy to them. RESULTS: Twenty-eight of 206 patients had positive patch test reactions to metals used in dentistry. The number of positive patch test reactions was highest for gold sodium thiosulfate, palladium chloride, and nickel sulfate (n = 10, respectively), followed by amalgam, ammoniated mercury, and cobalt chloride (n = 4, respectively) and amalgam-mixed metals (including copper, tin, zinc, and silicon), and ammonium tetrachloroplatinate (n = 1). Only 14 (7%) of 206 patients had a clinically relevant contact allergy with conditions of the oral mucosa (n = 7 with lichen planus and n = 7 with stomatitis) and positive patch test reactions to dental metals containing the suspected allergen. Improvement of symptoms was assessed in one patient with amalgam contact allergy 2 weeks after removal of dental fillings. CONCLUSIONS: Clinically relevant contact allergies to dental metals are infrequent. Gold sodium thiosulfate and palladium chloride presented the most frequent contact allergens.

The ability of disease modifying antirheumatic drugs to induce and maintain improvement in patients with rheumatoid arthritis. epidemiology of DMARDs treatment in Japan.

OBJECTIVE: The effectiveness of the disease-modifying antirheumatic drugs (DMARDs) methotrexate (MTX), bucillamine (BUC), salazosulphapyridine (SASP) and gold sodium thiomalate (GST) over two courses of treatment with a follow-up period of at least 12 months was evaluated in 425 patients with rheumatoid arthritis. METHODS: Clinical efficacy was evaluated on the basis of the numbers of painful and swollen joints, morning stiffness, grip strength, erythrocyte sedimentation rate, C-reactive protein and rheumatoid factor levels before and after treatment. Results were evaluated on the basis of the survival rate (Kaplan-Meier method) and the incidence and types of adverse drug reactions (ADR) following single and combined therapies. RESULTS: In the first course of treatment, the survival rates for MTX, GST, BUC and SASP were 52.3%, 40.4%, 33.0% and 24.8%, respectively. The rates of development of ADR were 22.9%, 23.5%, 26.3% and 30.0% for BUC, SASP, GST and MTX, respectively. In the second course, the survival rates for MTX, BUC and SASP were 36.6%, 14.1% and 10%, respectively. CONCLUSION: DMARDs used in the first course of treatment improved the clinical parameters until the 6th month after initiation of treatment. Combination treatments showed some effectiveness, but because of the high incidence of ADR the survival rate was low. DMARDs used in the second course of treatment were not efficacious and there was no improvement in the survival rate compared to the first course of treatment.

Fenoprofen, aspirin, and gold induction in rheumatoid arthritis.

Fenoprofen calcium (2,400 mg/day) or aspirin (3,900 mg/day) was administered in double-blind fashion to 20 rheumatoid patients during 6 months of gold induction therapy, and to 20 rheumatoid patients not receiving gold. Among both the gold-treated and nongold-treated patients, the fenoprofen and aspirin groups improved equally in all but one parameter of disease activity. Fenoprofen and aspirin did not differ significantly in the observed prevalences of abdominal discomfort, guaiac-positive stools, or peptic ulcers. Aspirin was associated with significantly higher mean serum glutamic oxaloacetic transaminase (SGOT) levels than fenoprofen, but only among patients undergoing gold induction. Comparison of efficacy parameters between patients treated with gold and patients treated with oral drugs alone revealed significant differences favoring gold.

Reversal of progressive, life-threatening gold hypersensitivity pneumonitis by corticosteroids.

Hypersensitivity pneumonitis secondary to gold therapy has been described in only a limited number of patients. The clinical presentation is variable and optimal therapy is not well established. Two patients presenting with life-threatening respiratory insufficiency that progressed despite discontinuation of gold therapy are described. Dramatic improvement occurred following corticosteroid administration. Review of previously reported cases shows corticosteroid therapy to be efficacious. Patients with gold hypersensitivity pneumonitis may have a fulminant course and many require corticosteroids for relief.

Association of IgE antibodies to sodium aurothiomalate and adverse reactions to chrysotherapy for rheumatoid arthritis.

The relationship between adverse reactions to chrysotherapy and specific IgE antibodies to sodium aurothiomalate (auIgE) was studied in 67 patients with rheumatoid arthritis (62) or psoriatic arthritis (5). Thirty patients (45 percent) had such antibodies versus none of the 27 control patients. Of the 34 patients in whom reactions to chrysotherapy developed, 23 (68 percent) had auIgE versus 7 (21 percent) without reactions (p less than 0.001). Mucocutaneous lesions were significantly associated with auIgE (p less than 0.001). All five patients with thrombocytopenia, but only one of five with the nephrotic syndrome, had auIgE. The patients with IgE response had higher total serum IgE levels (p less than 0.005), were more likely to be atopic (four to one), and had more recently received chrysotherapy (mean 2.8 +/- 1.95 years versus 7.0 +/- 5.75 years, p less than 0.001) than those without response, but did not differ by either the gold product or the total dose used. Chrysotherapy is associated with the production of specific IgE antibodies to a gold salt, and some mucocutaneous and hematologic reactions may be immunologically mediated.

Thrombocytopenia associated with gold therapy. Observations on the mechanism of platelet destruction.

Severe thrombocytopenia developed in a patient with rheumatoid arthritis during gold therapy. Increased numbers of marrow megakaryocytes, shortened 51Cr-labeled platelet survival and platelet phagocytosis by splenic macrophages indicated that thrombocytopenia was due to excessive platelet destruction. Aurothiomalate disodium antigenicity was demonstrated by increased lymphocyte blastogenesis, and accentuation of blood and splenic leukocyte migration in the presence of the gold salt. In vitro splenic immunoglobulin G (IgG) production was markedly increased, and a significant portion of the culture-produced IgG attached specifically to homologous platelets and platelet membranes. Serum antiplatelet antibodies could not be demonstrated, nor could it be shown that gold enhanced the binding of splenic-synthesized IgG to platelets. The data indicate an immunologic mechanism for gold-associated thrombocytopenia and permit speculation as to possible ways in which unidentified antigens may be involved in the pathogenesis in idiopathic thrombocytopenic purpura.

HLA-DR1-positive patients suffering from rheumatoid arthritis are at high risk for developing mucocutaneous side effects upon gold therapy.

Population studies suggest an association between RA and, depending on the ethnic background, HLA-DR1 and/or -DR4. One standard regimen for the treatment of RA is the use of gold compounds like SATM to arrest progression of the disease. In the present study, the immunogenetic background of RA patients developing side effects upon SATM treatment was determined. A total of 53 patients under SATM therapy were tested for their HLA-DRB and -DQ alleles by DNA typing; a significantly higher frequency of HLA-DR1 (p < 0.004, uncorrected) was observed in patients presenting with mucocutaneous side effects (MCT) when compared with patients without MCT. The RR was 6.85. Thus, HLA-DR1 seems to be a marker for the susceptibility of gold adverse reactions.

Gold induced thrombocytopenia: 12 cases and a review of the literature.

Gold induced thrombocytopenia is immune mediated, with the production of platelet associated IgG leading to peripheral platelet destruction. An association with HLA-DR3 has been demonstrated. Corticosteroid therapy is effective in treatment, although other modes of therapy may be as efficacious.

A double-blind comparison of parenteral methotrexate and parenteral gold in the treatment of early erosive rheumatoid arthritis: an interim report on 102 patients after 12 months.

One hundred two patients with active erosive rheumatoid arthritis (RA) without malalignment or deformities (median disease duration, 14 months) entered a double-blind, randomized study to compare the effects of 50 mg gold sodium thiomalate (GST) with 15 mg methotrexate (MTX) administered intramuscularly for 12 months. Roentgenograms of hands, wrists, and forefeet were taken at baseline and after 6 and 12 months, and 32 joints were evaluated according to Larsen. Sixteen of 50 patients in the MTX group were withdrawn; one patient in the MTX group died of cerebral bleeding that was not related to treatment. Thirty-four GST patients and 44 MTX patients were evaluated for efficacy. Thirty-eight joints were counted. The number oftender and swollen joints, the Lansbury articular index, morning stiffness, activities of daily living (ADL) score, and erythrocyte sedimentation rate improved significantly in both groups without statistical intergroup differences. After 12 months, there was a significant deterioration of the mean Larsen index and the number of joints with erosions without intergroup difference. However, the radiological progression was retarded significantly during the second 6-month period in the gold group, whereas this effect was less pronounced in the MTX group. At 12 months, the progression rate was the same in both groups.

Histocompatibility antigens in adult obliterative bronchiolitis with or without rheumatoid arthritis.

We compared HLA antigens in 28 patients with obliterative bronchiolitis (16 with rheumatoid arthritis) with those in 150 normal controls, to determine their relationship to drug toxicity and to the pathogenesis of obliterative bronchiolitis (OB). There was a significantly increased prevalence of HLA-B40 in the whole group and in patients with OB and rheumatoid arthritis (RA). There was increased frequency of HLA-A2 and A28 within the whole group and in those with OB alone. HLA-A3 and B5 were completely absent in our patients. Of those antigens most frequently associated with RA, DR4 was significantly more prevalent in patients with OB, with or without RA, but DR1 occurred more frequently only in those with RA-associated OB. Increased prevalence of DR4 may indicate an association between the pathogenesis of both OB and RA and the HLA-DR locus. Although D-penicillamine has been implicated in the pathogenesis of OB our patients did not show an increase in those antigens associated with other gold/penicillamine toxicity (i.e. DR2/3), suggesting that they may constitute a distinct group.

HLA-A,-B, and -DR antigens in relation to gold and D-penicillamine toxicity in Greek patients with RA.

Ninety-five rheumatoid arthritis patients treated with aurothiomalate and/or D-penicillamine have been studied for possible associations between HLA-A, -B, -DR antigens and various toxic reactions to the above drugs. HLA-DR3 and -DRw6 had a higher frequency in patients with toxic reactions (all types) than in patients without toxic reactions (28.5 per cent vs 13.0 per cent and 26.5 per cent vs 4.3 per cent, chi 2 = 2.6 and 7.2, respectively). HLA-B8 was found at a higher frequency in patients with proteinuria and other types of renal involvement (20.0 per cent vs 7.4 per cent in controls), whereas skin manifestations were mainly associated with the presence of HLA-DRw6. The lowest frequency of side-effects was seen in patients with HLA-DR1 and DR2 (10.2 per cent vs 28.3 per cent and 28.5 per cent vs 54.3 per cent, chi 2 = 3.9 and 5.5, respectively). In addition, seropositive patients possessing HLA-DR1, showed toxic reactions less frequently.

Bronchoalveolar lavage in gold lung.

We report the results of bronchoalveolar lavage in a patient with gold salt-induced interstitial pneumonitis. The presence of elevated numbers of lymphocytes in the lavage specimen supports a hypersensitivity-related pathogenesis of this disease. Such findings may help distinguish pulmonary complications of gold therapy from interstitial disease due to rheumatoid arthritis.

Patients with rheumatoid arthritis and gold-induced pneumonitis express two high-risk major histocompatibility complex patterns.

Gold salt therapy-induced pneumonitis is a rare complication in patients with rheumatoid arthritis (RA). We studied HLA-A, B, C, D/DR, and complement factor B (Bf) and C4 alleles in 17 patients with RA and gold-induced pneumonitis and found that these patients had strikingly homogeneous major histocompatibility complex (MHC) markers. Eight of them (47 percent) had the alleles HLA-A3 B35 Dwl BfF C4A3,2 (BO), which were shown by family studies of some patients to be inherited as an extended MHC-haplotype with an apparent gene duplication in the C4A locus. The other high-risk phenotype, HLA-B40 with a C4 null allele, was found in eight patients (47 percent). All but three of the 17 patients had at least one of the two high-risk markers, the frequency of these combinations being clearly higher than in the two control groups: patients with RA but with no gold-induced side effects and healthy individuals. Our study shows that use of several MHC markers together results in a strong association between the markers and the disease.