RESUMO
Ninety patients were entered into a randomized, controlled, double-blind trial lasting 12 months to compare auranofin (6 mg/d), and D-penicillamine (250 mg/d for 4 weeks, 500 mg/d for 4 weeks, then 750 mg/d thereafter) in the treatment of rheumatoid arthritis. Most patients in both groups completed the trial with significant improvement in all quantitative measures of efficacy. Patients treated with D-penicillamine were more likely to have "important improvement" in physician global assessment, swollen joint count, and score and grip strength. The overall frequency of side effects was similar between the two groups; however, more patients were withdrawn for adverse effects from the D-penicillamine group, and proteinuria (greater than or equal to 2+) and thrombocytopenia (less than 100 000 mm3) occurred significantly more frequently with D-penicillamine than auranofin (p = 0.028). These results suggest that in the dosage regimen used, auranofin is safer than D-penicillamine but that D-penicillamine tends to show greater clinical effectiveness in patients with rheumatoid arthritis.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Aurotioglucose/análogos & derivados , Ouro/análogos & derivados , Penicilamina/uso terapêutico , Auranofina , Aurotioglucose/efeitos adversos , Aurotioglucose/uso terapêutico , Ensaios Clínicos como Assunto , Método Duplo-Cego , Feminino , Humanos , Articulações/patologia , Masculino , Pessoa de Meia-Idade , Movimento , Penicilamina/efeitos adversos , Distribuição AleatóriaRESUMO
These studies were designed to investigate the effects of the chrysotherapeutic agents auranofin and myochrysine (GST) on hepatic and renal drug-metabolizing enzymes and heme metabolism. Male Sprague-Dawley rats were either administered a single dose of auranofin (17, 34, or 68 mg/kg, p.o.) or administered daily doses of auranofin (0.2, 0.6, 2, 9, or 40 mg/kg/day, p.o.) or GST (1.2 or 5.8 mg/kg/day, i.p.) for 3 or 14 days. Rats were killed 24 h after the final treatment, and subcellular fractions of liver and kidney were prepared. Cytochrome P-450 (P-450) content and ethoxycoumarin-O-deethylase (ECOD), benzphetamine-N-demethylase (BPND), delta-aminolevulinic acid (ALA) synthetase, and heme oxygenase activities were determined. Twenty-four hours following single doses of auranofin, no effects on hepatic P-450, ECOD, or BPND were observed. Treatment with the positive control compounds, CoCl2 (60 mg/kg) and Co-protophorphyrin IX (33 mg/kg), produced decreases in all three variables at 24 hr. Auranofin, at 2 mg/kg, and GST treatment, at both doses, reduced hepatic P-450 and ECOD activity at 3 days. This effect was reversed with continued treatment for 14 days. BPND activity was unaffected at 3 days but was decreased at 14 days. Heme oxygenase activity was enhanced at 3 days and had returned to control activity at 14 days, while ALA synthetase was unaffected. With the exception of heme oxygenase, which was increased, renal variables were unaltered at 3 days. At 14 days, renal P-450 content was decreased in the high-dose auranofin group, heme oxygenase activity was increased in all groups, and ALA synthetase activity was elevated in high-dose auranofin animals. These data indicate that, at doses twenty times the human dose, auranofin and GST administration produced reversible decreases in hepatic and renal P-450 which may be the result of altered heme metabolism.
Assuntos
Aurotioglucose/análogos & derivados , Tiomalato Sódico de Ouro/farmacologia , Ouro/análogos & derivados , Heme/metabolismo , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , 5-Aminolevulinato Sintetase/metabolismo , O-Dealquilase 7-Alcoxicumarina , Animais , Auranofina , Aurotioglucose/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Rim/enzimologia , Fígado/enzimologia , Masculino , Oxirredutases N-Desmetilantes/metabolismo , Oxigenases/metabolismo , Ratos , Fatores de TempoRESUMO
The effect of sodium aurothiomalate and auranofin on the generation of superoxide anions (O2-) by polymorphonuclear leukocytes (PMNLs) and adherent mononuclear phagocytic cells (AMNCs) has been investigated. Sodium aurothiomalate at final concentrations of 1, 10, and 100 micrograms Au/ml and auranofin ranging from 0.1 to 2.0 micrograms Au/ml were used in the reactions involving all cell types. Results have been compared between cells drawn from normal controls and patients with active rheumatoid disease. The effect of gold compounds on both cell types was assessed following activation by phorbol myristate acetate (1 X 10(-8) M) and N-formyl-methionyl-leucyl-phenylalanine (1 X 10(-4) M) using a cytochrome c reduction method. Sodium aurothiomalate at the maximum concentration modestly inhibited O2- generation by PMNLs but not AMNCs. Auranofin inhibits O2- generation by both cell types. Inhibition of cells from patients with rheumatoid arthritis was greater than that seen with cells from normal controls.
Assuntos
Artrite Reumatoide/fisiopatologia , Aurotioglucose/análogos & derivados , Tiomalato Sódico de Ouro/farmacologia , Ouro/análogos & derivados , Monócitos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Superóxidos/biossíntese , Artrite Reumatoide/tratamento farmacológico , Auranofina , Aurotioglucose/farmacologia , Depressão Química , Humanos , Monócitos/metabolismo , Neutrófilos/metabolismo , Fagocitose/efeitos dos fármacosRESUMO
The inhibitory effects of gold compounds on the NADPH oxidase system of human polymorphonuclear leukocytes (PMNs) has been investigated. Auranofin (0.5-4.0 micrograms Au/ml) suppressed the rate of superoxide anion generation as well as the total yield in cells stimulated with phorbol myristate acetate and f-Met-Leu-Phe. This implies that drug action may be occurring at the level of protein kinase C or steps subsequent to this in the signal transduction sequence. Sodium aurothiomalate (1-100 micrograms Au/ml) lacked such activity. Neither gold compound altered the ability of the granule-rich fraction of PMNs to produce oxy radicals whether this fraction was obtained from drug-treated cells or was treated after its isolation. Therefore, in order for auranofin to exhibit its inhibitory effects on the NADPH oxidase system, an intact cell membrane is necessary.
Assuntos
Aurotioglucose/análogos & derivados , Tiomalato Sódico de Ouro/farmacologia , Ouro/análogos & derivados , Proteínas de Membrana/antagonistas & inibidores , NADH NADPH Oxirredutases/antagonistas & inibidores , Neutrófilos/enzimologia , Auranofina , Aurotioglucose/farmacologia , Grânulos Citoplasmáticos/enzimologia , Radicais Livres , Humanos , N-Formilmetionina Leucil-Fenilalanina/farmacologia , NADPH Oxidases , Superóxidos/biossíntese , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
Twenty-three patients with severe longstanding discoid lupus erythematosus, unresponsive to conventional treatments, were treated with oral gold in a multicentre open study. Nineteen patients showed clinical improvement and in four of these there was complete resolution of lesions. Adverse reactions were generally mild and self limiting.
Assuntos
Aurotioglucose/análogos & derivados , Ouro/análogos & derivados , Lúpus Eritematoso Discoide/tratamento farmacológico , Adolescente , Adulto , Idoso , Auranofina , Aurotioglucose/efeitos adversos , Aurotioglucose/uso terapêutico , Doença Crônica , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeAssuntos
Artrite Reumatoide/tratamento farmacológico , Aurotioglucose/análogos & derivados , Ouro/análogos & derivados , Administração Oral , Adulto , Auranofina , Aurotioglucose/administração & dosagem , Aurotioglucose/efeitos adversos , Aurotioglucose/uso terapêutico , Diarreia/induzido quimicamente , Ouro/administração & dosagem , Humanos , InjeçõesRESUMO
In vitro exposure of cultured human, murine and rat cells to pharmacologic concentrations (10(-8) to 10(-6) M) of auranofin, 2,3,4,6,-tetra-O-acetyl-1-thio-beta-D-glucopyranosato-S- triethylphosphine gold(I) (Ridaura), a gold containing compound approved for the treatment of rheumatoid arthritis, results in the induction of several stress proteins. The enhanced synthesis of two polypeptides, p32 and p34, was particularly prominent. A similar response was observed in freshly collected human monocytes challenged with auranofin. In addition, oral administration of auranofin to rats induced enhanced synthesis of a 32-kDa protein in peritoneal exudate cells analyzed ex vivo at various times following drug treatment. These data suggest that increased synthesis of p32 and p34 might participate in mediating certain aspects of auranofin pharmacology.
Assuntos
Aurotioglucose/análogos & derivados , Ouro/análogos & derivados , Proteínas de Choque Térmico/biossíntese , Animais , Artrite Reumatoide/tratamento farmacológico , Auranofina , Aurotioglucose/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Camundongos , Peso Molecular , Monócitos/efeitos dos fármacos , Cavidade Peritoneal/citologia , Ratos , Especificidade da EspécieRESUMO
Mucosal auranofin (AF) caused a concentration dependent inhibition of fluid, Na+, glycine and galactose transport by everted sacs of rat small intestine (IC50 = 2 X 10(-4) M). Inhibition of nutrient absorption was not due to reduced fluid uptake since a similar reduction in fluid uptake induced by a mucosal osmotic load failed to alter glycine transport. Inhibitory effects of AF were not observed when metabolism was reduced, suggesting that carrier mediated entry processes were unaltered. AF inhibited Na+, K+-ATPase activity in isolated enterocytes (IC50 = 2 X 10(-4) M), without affecting Mg2+-dependent ATPase activity. Our studies suggest that the actions of AF on small intestinal absorption may result from inhibition of the Na+ pump.
Assuntos
Aurotioglucose/análogos & derivados , Ouro/análogos & derivados , Intestino Delgado/metabolismo , Adenosina Trifosfatases/metabolismo , Animais , Auranofina , Aurotioglucose/efeitos adversos , Aurotioglucose/farmacologia , Transporte Biológico/efeitos dos fármacos , Diarreia/induzido quimicamente , Absorção Intestinal/efeitos dos fármacos , Intestino Delgado/enzimologia , Masculino , RatosAssuntos
Anti-Inflamatórios/uso terapêutico , Artrite/tratamento farmacológico , Aurotioglucose/análogos & derivados , Ouro/análogos & derivados , Psoríase/tratamento farmacológico , Administração Oral , Anti-Inflamatórios/administração & dosagem , Auranofina , Aurotioglucose/administração & dosagem , Aurotioglucose/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
Auranofin in the mucosal fluid caused a dose-dependent inhibition of fluid and Na+ absorption by everted sacs of rat colon. Serosal auranofin was without effect. (Na+ + K+)ATPase activity of homogenates of mucosal scrapes of rat colon was inhibited by auranofin in a dose-related manner, while Mg2+-ATPase activity was little affected. These actions of the drug on colonic transport mechanisms could contribute to the diarrhoea associated with auranofin therapy.
Assuntos
Anti-Inflamatórios/farmacologia , Aurotioglucose/análogos & derivados , Colo/metabolismo , Ouro/análogos & derivados , Sódio/metabolismo , Adenosina Trifosfatases/metabolismo , Animais , Auranofina , Aurotioglucose/farmacologia , Transporte Biológico/efeitos dos fármacos , Mucosa Intestinal/enzimologia , Masculino , RatosRESUMO
Radioimmunoassay (RIA) and reversed-phase high-pressure liquid chromatography (HPLC) were used to investigate gold-binding proteins of possible metallothionein (MT) nature occurring upon auranofin exposure of cultured human cells. An epithelial cell line (HE) and two sub-strains were examined. The HEAF sub-strain had been made resistant to 2 mumole auranofin/l culture medium. The resistance was associated with the appearance of gold-binding substances with gel filtration characteristics like MT. The HE100 sub-strain had been made resistant to 100 mumole CdCl2/l and contained high amounts of cytosolic Cd-induced MT. In addition, cultured synovial fibroblasts, derived from normal (SN) and rheumatoid (SRA) synovial tissues, were investigated. Evidence was obtained by RIA that the low molecular weight (mol.wt. 6000-7000) gold-binding proteins occurring in the HEAF cells and SRA cells following auranofin exposure, were of MT nature. The relative amounts of MT in the epithelial cell lines were: HE:HEAF:HE100 = 1:18:100. The relative amounts in the synovial fibroblasts were: SN:SRA:SRA treated with auranofin = 1:3:10. The HPLC methods used were found suitable for isolation of Cd-MT in the HE100 cells, but not for the Au-MT in the HEAF cells. By HPLC, the Cd-MT in the HE100 cells was resolved into 3 MT-1 and 1 MT-2 iso-proteins exhibiting the amino acid composition typical of MT. Judged by HPLC, the MT in these cells constituted 0.4% of the cytosolic proteins.
Assuntos
Anti-Inflamatórios/farmacologia , Artrite Reumatoide/metabolismo , Aurotioglucose/análogos & derivados , Ouro/análogos & derivados , Metalotioneína/análise , Membrana Sinovial/análise , Aminoácidos/análise , Auranofina , Aurotioglucose/farmacologia , Cádmio/metabolismo , Células Cultivadas , Cromatografia em Gel , Cromatografia Líquida de Alta Pressão , Epitélio/análise , Fibroblastos/análise , Humanos , Concentração de Íons de Hidrogênio , RadioimunoensaioRESUMO
A patient with severe rheumatoid arthritis and sicca symptoms was treated with auranofin. During auranofin therapy, she developed irreversible airways obstruction due to bronchiolitis. Whereas this complication could have been due to her underlying disease, we discuss here the possibility of its being related to the auranofin therapy.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Aurotioglucose/análogos & derivados , Bronquite/induzido quimicamente , Ouro/análogos & derivados , Adulto , Auranofina , Aurotioglucose/efeitos adversos , Aurotioglucose/uso terapêutico , Feminino , HumanosRESUMO
Auranofin (AF) a new antiarthritic gold compound effective when administered orally, frequently causes diarrhea with abnormal stool electrolyte content. Studies were designed to determine the mechanism of the diarrhea caused by AF. In perfused canine Thiry-Vella loops, AF caused significant elevations in effluent volume, osmolarity, and sodium concentration and a significant decrease in potassium concentration. In mucosal homogenates of rat small bowel, AF inhibited sodium, potassium ATPase in a concentration dependent manner. AF did not alter canine colonic smooth muscle activity in vitro. We suggest that AF induced diarrhea results from interruption of normal water and electrolyte absorption by inhibition of enterocyte sodium, potassium ATPase activity.
Assuntos
Aurotioglucose/análogos & derivados , Diarreia/induzido quimicamente , Eletrólitos/metabolismo , Compostos de Ouro , Ouro/análogos & derivados , Jejuno/efeitos dos fármacos , Água/metabolismo , Animais , Auranofina , Aurotioglucose/farmacologia , Aurotioglucose/toxicidade , ATPase de Ca(2+) e Mg(2+)/antagonistas & inibidores , Cloretos/farmacologia , Colo/efeitos dos fármacos , Colo/fisiopatologia , Diarreia/metabolismo , Cães , Motilidade Gastrointestinal/efeitos dos fármacos , Ouro/farmacologia , Tiomalato Sódico de Ouro/farmacologia , Jejuno/metabolismo , Ratos , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidoresRESUMO
In these experiments the effects of pharmacological concentrations of auranofin, a new absorbable gold compound, were assessed on the release of histamine and peptide leukotriene C4 (LTC4) from human basophils and lung mast cells. Auranofin, at pharmacological concentrations, inhibited in vitro histamine and LTC4 release from human basophils induced by anti-IgE. Inhibition began at about 3 X 10(-7) M and was maximum at 10(-5) M. We also evaluated the effect of auranofin on the release of histamine and LTC4 induced by anti-IgE from mast cells purified from human lung. Auranofin (3 X 10(-7) to 10(-5) M) dose-dependently inhibited the release of histamine and LTC4 from human lung mast cells. Thus pharmacological concentrations of auranofin cause dose-related inhibition of histamine release and de novo synthesis of LTC4 by human basophils and lung mast cells.
Assuntos
Anti-Inflamatórios/farmacologia , Aurotioglucose/análogos & derivados , Basófilos/metabolismo , Ouro/análogos & derivados , Liberação de Histamina/efeitos dos fármacos , Mastócitos/metabolismo , SRS-A/metabolismo , Adulto , Auranofina , Aurotioglucose/farmacologia , Basófilos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Imunoglobulina E/imunologia , Técnicas In Vitro , Mastócitos/efeitos dos fármacosRESUMO
Auranofin, an orally gold preparation, effective in the treatment of rheumatoid arthritis, was found to be a potent noncytotoxic inhibitor of histamine and collagenase release from mast cells and polymorphonuclear (PMN) leukocytes respectively. Histamine release has been inhibited by auranofin in dose-dependent fashion. Auranofin at concentration of 10(-5) M inhibited 100% of the release, lower concentration 10(-6) M and 10(-7) M produced 80 and 40% decrease. The exposure of PMN-leukocytes to auranofin caused also dose-dependent inhibition of collagenase release. Auranofin at a concentration of 10(-4) M produced a marked reduction (75-100%) of enzyme release from human and rat blood PMN-leukocytes. The modest inhibition 40 and 15-20% at a concentration of 10(-5) M and 10(-6) M respectively was obtained. Auranofin more significantly suppressed collagenase release from leukocytes isolated from inflammatory exudate. Decrease of 100, 80 and 60% were observed upon addition of 10(-4) M, 10(-5) M and 10(-6) M of auranofin. These results suggest that therapeutic action of auranofin may be caused, at least in part, by the inhibition of cellular release of histamine and collagenase in the course of inflammation.
Assuntos
Anti-Inflamatórios/farmacologia , Aurotioglucose/análogos & derivados , Ouro/análogos & derivados , Liberação de Histamina/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Colagenase Microbiana/metabolismo , Neutrófilos/efeitos dos fármacos , Animais , Auranofina , Aurotioglucose/farmacologia , Relação Dose-Resposta a Droga , Humanos , Técnicas In Vitro , Mastócitos/metabolismo , Neutrófilos/enzimologia , RatosRESUMO
The pharmacokinetics of oral gold (auranofin) in some respects resemble, and in other respects differ from, those of existing parenteral gold compounds such as gold sodium thiomalate (GST). This may in part relate to physicochemical differences as GST is a water-soluble polymeric compound in vitro whereas auranofin is lipid-soluble and characteristically monomeric. Furthermore, intramuscularly administered gold is greater than 95% bioavailable, whereas only 20 to 30% of an orally administered dose of auranofin is absorbed. Following a standard 50mg intramuscular injection of GST, serum gold concentrations rise sharply, peaking between 4 and 8 mg/L in approximately 2 hours and declining to an average of 3 mg/L by 7 days. With repeated injections of GST stable serum concentrations of gold (3 to 5 mg/L) are eventually achieved (usually within 5 to 8 weeks) although absolute concentrations may vary widely between patients. On the other hand, long term treatment with auranofin is associated with lower and more stable serum concentrations of gold (0.5 to 0.7 mg/L), on the standard dosing regimen of 6 mg daily. Both compounds are retained within the body for prolonged periods. However, the amount of gold retained with auranofin is significantly less compared with GST (less than 5% of a tracer dose of auranofin--about 20% of the absorbed dose--is retained by 100 days whereas the retention for a single labelled dose of GST over a similar interval is greater than 50%). Excretory patterns of GST and auranofin also differ. Most of an absorbed dose of GST (greater than 70%) is excreted by the kidneys whereas only 50% of an absorbed (15% of an administered) dose of auranofin is excreted in the urine. Both compounds are avidly bound by plasma proteins and auranofin shows a particularly strong association with circulating cellular elements. In human subjects, parenterally administered gold is widely distributed among bodily tissues, showing a predilection for tissues of the reticuloendothelial system as well as the kidney and adrenal cortex. Comparable studies in humans are not available for auranofin but animal studies have shown comparatively less affinity for the liver, kidney and spleen. Valuable insight has been gained in analysing the comparative pharmacokinetics of oral and injectable gold compounds. Unfortunately, attempts to correlate pharmacokinetic findings with clinical response or pharmacodynamic changes, as a whole, remain largely unsuccessful with these agents.