RESUMEN
The inhibitor of NF-kappaB (IkappaB) kinases (IKK1[alpha] and IKK2[beta]), the catalytic subunits of the IKK complex, phosphorylate IkappaB proteins on serine residues, targeting them for degradation and thus activating the transcription factor NF-kappaB. More recently, IKK2 has been implicated in mediation of insulin resistance caused by obesity, lipid infusion, and TNF-alpha stimulation, since salicylate and aspirin, known inhibitors of IKK activity, can reverse insulin resistance in obese mouse models. To further genetically elucidate the role of IKK2 in obesity-mediated insulin resistance, we have conditionally inactivated the mouse IKK2 gene in adult myocytes by Cre-loxP-mediated recombination in vivo. We have investigated the development of obesity-induced insulin resistance in muscle-specific IKK2 knockout mice and mice exhibiting a 50% reduction of IKK2 expression in every tissue and have found that, after gold thioglucose treatment, wild-type and mutant mice developed obesity to a similar extent. Surprisingly, no difference in obesity-induced insulin resistance was detectable, either at a physiological or at a molecular level. Moreover, impaired glucose tolerance resulting from a high-fat diet occurred to the same degree in control and IKK2 mutant mice. These data argue against a substantial role for muscular IKK2 in mediating obesity-induced insulin resistance in these models in vivo.
Asunto(s)
Resistencia a la Insulina/fisiología , Obesidad/enzimología , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Aurotioglucosa/metabolismo , Quinasa I-kappa B , Insulina/metabolismo , Ratones , Músculo Esquelético/enzimología , Músculo Esquelético/metabolismo , Obesidad/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal/fisiologíaRESUMEN
Nuclear factor kappa B (NF-kappa B) is a transcription factor that is critical for the inducible expression of multiple cellular and viral genes. DNA binding activity is essential for its function. Here, we report that gold compounds, especially aurothioglucose (AuTG), have a strong inhibitory effect on NF-kappa B-DNA binding. Our finding also reveals that Zn2+ is a necessary component of NF-kappa B for its DNA binding activity and that gold ion can efficiently block NF-kappa B-DNA binding, presumably through oxidation of the cysteins associated with zinc. This redox mechanism may provide an explanation for the observed efficacy of gold compounds in the treatment of rheumatoid arthritis.
Asunto(s)
Aurotioglucosa/metabolismo , ADN/metabolismo , Compuestos de Oro/metabolismo , FN-kappa B/metabolismo , Aurotioglucosa/farmacología , Secuencia de Bases , Unión Competitiva , Quelantes/farmacología , Compuestos de Oro/farmacología , Modelos Biológicos , Datos de Secuencia Molecular , FN-kappa B/aislamiento & purificación , Oxidación-Reducción , Unión Proteica/efectos de los fármacos , Zinc/metabolismoRESUMEN
Aurothioglucose and aurothiomalate have anti-HIV-1 activity in vitro. Antiviral activity requires the formation of a reactive intermediate with a molar equivalent amount of a thiol ligand. This activates gold(I) ligand exchange between the reactive species bis(thiolato)gold(I) and acidic thiol groups exposed on the surface of proteins. Bis(thioglucose)gold(I) (bisAuTG) which is formed by the reaction of molar equivalent amounts of aurothioglucose and 1-thio-beta-D-glucose completely protected MT-4 and CEM cells against HIV-1NL4-3-induced cytopathogenicity. Although bisAuTG is an inhibitor of human immunodeficiency virus-1 (HIV-1) reverse transcriptase in a cell-free assay, its antiviral effect is due to modification of a surface component of the virion. The HIV-1 strain NL4-3 is 200-fold more sensitive to inhibition of infectivity by bisAuTG than are the strains MN, RF, and SF-2. HIV-1NL4-3 has a unique cysteine residue close to the amino terminus of its gp41 envelope glycoprotein (residue 532 of gp160) which we hypothesize is the target of bisAuTG binding. Mutation of that residue alters HIV-1NL4-3 infectivity and dominantly suppresses virus assembly when coexpressed with the wild-type NL4-3 genome. We show that bisAuTG treatment releases gp120 from the surface of cells expressing wild-type HIV-1NL4-3 envelope glycoprotein, but it does not release gp120 if Cys532 is mutationally altered to Ala. Thus, the antiviral effect of bisAuTG on HIV-1NL4-3 is due to an effect on the association of gp120 with gp41.
Asunto(s)
Antivirales/metabolismo , Antivirales/farmacología , Aurotioglucosa/metabolismo , Aurotioglucosa/farmacología , Oro/farmacología , Proteína gp120 de Envoltorio del VIH/genética , Proteína gp41 de Envoltorio del VIH/genética , VIH-1/efectos de los fármacos , Compuestos Organometálicos/farmacología , Virión/efectos de los fármacos , Secuencia de Aminoácidos , Secuencia de Bases , Línea Celular , Cisteína , Células Gigantes/citología , Células Gigantes/efectos de los fármacos , Tiomalato Sódico de Oro/farmacología , Proteína gp41 de Envoltorio del VIH/biosíntesis , VIH-1/patogenicidad , VIH-1/fisiología , Humanos , Cinética , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Oligodesoxirribonucleótidos , Compuestos Organometálicos/metabolismo , Provirus/efectos de los fármacos , Provirus/patogenicidad , Provirus/fisiología , Relación Estructura-Actividad , Factores de Tiempo , Células Tumorales Cultivadas , Virión/patogenicidad , Virión/fisiologíaRESUMEN
Auranofin (AF), an orally active, antiarthritic agent, modulates the functional activities of macrophages in vivo and in vitro. To better understand the molecular mechanism of action of auranofin with macrophages we have investigated its cellular association, intracellular distribution, and efflux with RAW 264.7 cells using auranofin radiolabeled within the triethylphosphine (Et3P) [3H], the gold [195Au] or the tetraacetylthioglucose (TATG)[14C] moieties of the molecule. Evaluation of the effects of auranofin on RAW 264.7 cells demonstrates that (1) cellular association of this compound was concentration, time and temperature dependent; (2) cellular association of AF was inhibited by N-ethylmaleimide but not by 2,4-dinitrophenol and NaF; (3) cellular association and uptake of Au and Et3P into cells was reduced when the drug was preincubated with increasing concentrations of fetal calf serum and albumin; (4) no tetraacetylthioglucose from the auranofin molecule became cell associated whereas the Au and Et3P moieties were internalized and distributed between the nuclear, cytosolic and membrane fractions of cells; and (5) efflux of Au and Et3P from RAW 264.7 cells was time and temperature dependent. Based on these data we propose a model, a sequential ligand exchange process, that describes the molecular interactions of auranofin and possibly other gold compounds with these cells.
Asunto(s)
Antiinflamatorios/metabolismo , Aurotioglucosa/análogos & derivados , Oro/análogos & derivados , Macrófagos/metabolismo , 2,4-Dinitrofenol , Animales , Auranofina , Aurotioglucosa/metabolismo , Proteínas Sanguíneas/metabolismo , Radioisótopos de Carbono , Células Cultivadas , Citosol/metabolismo , Dinitrofenoles/farmacología , Etilmaleimida/farmacología , Radioisótopos de Oro , Ligandos , Macrófagos/ultraestructura , Ratones , Unión Proteica , Fluoruro de Sodio/farmacología , Compuestos de Sulfhidrilo/farmacología , Temperatura , TritioRESUMEN
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.
Asunto(s)
Aurotioglucosa/análogos & derivados , Tiomalato Sódico de Oro/metabolismo , Oro/análogos & derivados , Administración Oral , Auranofina , Aurotioglucosa/administración & dosificación , Aurotioglucosa/metabolismo , Disponibilidad Biológica , Tiomalato Sódico de Oro/administración & dosificación , Semivida , Humanos , Inyecciones Intramusculares , Absorción Intestinal , Cinética , Unión Proteica , Solubilidad , Líquido Sinovial/metabolismo , Distribución TisularAsunto(s)
Anomalías Inducidas por Medicamentos/prevención & control , Artritis Reumatoide/tratamiento farmacológico , Aurotioglucosa/efectos adversos , Oro/efectos adversos , Complicaciones del Embarazo/tratamiento farmacológico , Adulto , Animales , Aurotioglucosa/metabolismo , Lactancia Materna , Femenino , Humanos , Recién Nacido , Intercambio Materno-Fetal , Embarazo , Ratas , TeratógenosAsunto(s)
Artritis Reumatoide/tratamiento farmacológico , Aurotioglucosa/análogos & derivados , Oro/análogos & derivados , Auranofina , Aurotioglucosa/efectos adversos , Aurotioglucosa/metabolismo , Aurotioglucosa/uso terapéutico , Ensayos Clínicos como Asunto , Oro/uso terapéutico , Humanos , CinéticaAsunto(s)
Antiinflamatorios , Aurotioglucosa/análogos & derivados , Tiomalato Sódico de Oro , Oro/análogos & derivados , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Auranofina , Aurotioglucosa/administración & dosificación , Aurotioglucosa/metabolismo , Aurotioglucosa/farmacología , Fenómenos Químicos , Química , Tiomalato Sódico de Oro/administración & dosificación , Tiomalato Sódico de Oro/metabolismo , Tiomalato Sódico de Oro/farmacología , Humanos , RatasRESUMEN
The possibility of development of adaptation to intestinal adverse effects of auranofin (AF), a gold-containing anti-arthritic drug, was investigated in rats. Groups of 6 rats received orally 0.0, 2.5 or 10.0 mg AF/kg daily for one week, and 20.0 mg AF/kg daily the next week. During the first week all animals had normal stools. During the second week, those on 0.0 or 2.5 mg AF/kg the preceding week developed persistent loose stools, whereas those on 10.0 mg AF/kg the preceding week did not. At the end of the second week, no differences in the intestinal cytosolic gold concentrations were detected, which could be related to the dose regimen or the loose stools. Gel filtration profiles of gold from intestinal, liver and kidney cytosols following AF treatment, were compared with gold profiles following in vitro incubation of AF with cytosols obtained from non-treated rats. In the in vivo situation, but not in vitro, gold peaked with proteins of mol. wt. about 10,000 in the small intestine and kidneys. Up to 20% of the cytosolic gold was recovered in these fractions in the small intestine. These proteins eluted slightly different from metallothionein on gel filtration. The cellular mechanisms involved in the demonstrated adaptation to intestinal adverse effects from AF, are not clear, judged from the present study.
Asunto(s)
Aurotioglucosa/análogos & derivados , Citosol/metabolismo , Diarrea/inducido químicamente , Oro/análogos & derivados , Mucosa Intestinal/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Animales , Auranofina , Aurotioglucosa/metabolismo , Aurotioglucosa/toxicidad , Relación Dosis-Respuesta a Droga , Femenino , Ratas , Ratas Endogámicas , Distribución TisularAsunto(s)
Antiinflamatorios/metabolismo , Artritis Reumatoide/tratamiento farmacológico , Aurotioglucosa/análogos & derivados , Tiomalato Sódico de Oro/metabolismo , Oro/análogos & derivados , Formación de Anticuerpos/efectos de los fármacos , Auranofina , Aurotioglucosa/efectos adversos , Aurotioglucosa/metabolismo , Aurotioglucosa/farmacología , Aurotioglucosa/uso terapéutico , Tiomalato Sódico de Oro/efectos adversos , Tiomalato Sódico de Oro/farmacología , Tiomalato Sódico de Oro/uso terapéutico , Humanos , Inmunidad Celular/efectos de los fármacos , CinéticaAsunto(s)
Antiinflamatorios/administración & dosificación , Aurotioglucosa/análogos & derivados , Oro/análogos & derivados , Administración Oral , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Auranofina , Aurotioglucosa/administración & dosificación , Aurotioglucosa/metabolismo , Aurotioglucosa/farmacología , HumanosRESUMEN
The concentrations of gold in whole blood, serum, urine and blood cells of patients with rheumatoid arthritis were measured during 6 months of oral treatment either with Auranofin or placebo. Any adverse effects attributable to the treatments were also recorded. Although the time course of gold during Auranofin therapy was similar to that of injected gold, the blood and serum gold concentrations were significantly lower than those measured in patients receiving injected gold. Between 45 and 58% of Auranofin gold in the blood was associated with blood cells. In comparison, following injections of gold thiomalate, only about 4% of the gold was present in the blood cells. During the 6-month period, 2 patients receiving Auranofin withdrew because of diarrhoea and another because of rash. 1 placebo patient withdrew because of headaches. No laboratory evidence of haematological, renal or hepatic abnormality was encountered. It is suggested that the markedly lower concentrations of gold in the body sustained during treatment with Auranofin may be the critical factor towards a greater tolerance of the drug in the treatment of rheumatoid arthritis.
Asunto(s)
Aurotioglucosa/análogos & derivados , Oro/análogos & derivados , Oro/metabolismo , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Auranofina , Aurotioglucosa/efectos adversos , Aurotioglucosa/metabolismo , Aurotioglucosa/uso terapéutico , Tiomalato Sódico de Oro/efectos adversos , Tiomalato Sódico de Oro/metabolismo , Tiomalato Sódico de Oro/uso terapéutico , Humanos , Persona de Mediana Edad , Factores de TiempoAsunto(s)
Antiinflamatorios/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Aurotioglucosa/análogos & derivados , Oro/análogos & derivados , Administración Oral , Corticoesteroides/uso terapéutico , Antiinflamatorios/administración & dosificación , Antiinflamatorios/metabolismo , Aspirina/uso terapéutico , Auranofina , Aurotioglucosa/administración & dosificación , Aurotioglucosa/metabolismo , Aurotioglucosa/uso terapéutico , Evaluación de Medicamentos , Quimioterapia Combinada , Tiomalato Sódico de Oro/uso terapéutico , Humanos , Inyecciones IntramuscularesRESUMEN
Auranofin, 2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranosato-S-(triethy lphosphine)- gold(I), an experimental antiarthritis pharmaceutical, metabolized in contact with hamster or rat gut wall to yield the deacetylated form of the drug. This product, 1-thio-beta-D-glucopyranosato-S-(triethylphosphine)gold(I), passed through hamster or rat intestinal wall in an everted gut experiment. The metabolite was separated by high-performance liquid chromatography and characterized by retention time, chemical reactivity to yield a known product, and comparison to a synthetic sample of the metabolite.
Asunto(s)
Antiinflamatorios/metabolismo , Aurotioglucosa/análogos & derivados , Oro/análogos & derivados , Absorción Intestinal , Animales , Auranofina , Aurotioglucosa/metabolismo , Cromatografía Líquida de Alta Presión , Cricetinae , Mesocricetus , Ratas , Ratas EndogámicasRESUMEN
The tissue and subcellular pharmacokinetics of gold following single and repeated oral doses of triethylphosphine gold (auranofin) has been studied in rats. After a single dose, the tissue and subcellular gold levels were 5-10 times lower than those reached with injectable gold compounds. In the liver tissues, gold concentrations peaked within 24 h followed by a biphasic clearance, with an initial rapid phase (t1/2 32 h) and a slow terminal phase (t 1/2 11 days). Renal gold concentrations continued to increase for 3 to 5 days and then decreased exponentially with a first order t 1/2 of about 7 days. Intracellularly, between 60-80% of hepatic and 50-70% of renal gold was present in the cytosol. In rats given repeated doses of auranofin, the hepatic and renal gold concentrations were 3-5 times higher than those measured after a single dose. The proportion of cellular gold present in the cytosol was markedly lower, with 43% in the liver and 30% in kidney tissues. In both the liver and kidney, gold concentrations were dose-dependent, whereas in the gastrointestinal tissues the increases as a function of dose were minimal.
Asunto(s)
Antiinflamatorios/metabolismo , Aurotioglucosa/análogos & derivados , Oro/análogos & derivados , Administración Oral , Animales , Antiinflamatorios/administración & dosificación , Auranofina , Aurotioglucosa/administración & dosificación , Aurotioglucosa/metabolismo , Citosol/metabolismo , Riñón/metabolismo , Cinética , Hígado/metabolismo , Masculino , Ratas , Ratas EndogámicasRESUMEN
Auranofin is the first orally active gold compound for the treatment of rheumatoid arthritis. Like other chrysotherapeutic agents, its exact mechanism of action is unknown, but it probably acts via immunological mechanisms and alteration of lysosomal enzyme activity. Although long term clinical experience with auranofin is limited, its efficacy appears to approach that of sodium aurothiomalate. Further comparative studies with aurothioglucose, hydroxychloroquine and D-penicillamine are required before definitive statements can be made regarding the relative efficacy of auranofin and these agents. While patients have demonstrated clinical remission of rheumatoid arthritis in response to auranofin therapy, radiological studies have been inconclusive regarding its effect on the occurrence or progression of erosive lesions. Auranofin is relatively well tolerated in most patients, but diarrhoea, skin rash, and pruritus are sometimes troublesome, and thrombocytopenia and proteinuria are potentially serious side effects which may occur during therapy. Whereas mucocutaneous side effects are more frequent with injectable gold compounds, gastrointestinal reactions are the most common adverse effect seen with auranofin. The frequency of side effects has been similar with auranofin and sodium aurothiomalate, but they are generally less severe with auranofin. While some of the side effects are controlled by a reduction in dosage, temporary or permanent withdrawal of auranofin may be necessary. Auranofin is clearly a useful addition to the limited list of agents with disease-modifying potential presently available for the treatment of rheumatoid arthritis. It will doubtless generate much interest as its final place in therapy becomes better defined through additional well-designed studies and wider clinical experience.
Asunto(s)
Antiinflamatorios/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Aurotioglucosa/análogos & derivados , Oro/análogos & derivados , Absorción , Animales , Auranofina , Aurotioglucosa/efectos adversos , Aurotioglucosa/inmunología , Aurotioglucosa/metabolismo , Aurotioglucosa/uso terapéutico , Ensayos Clínicos como Asunto , Diarrea/inducido químicamente , Relación Dosis-Respuesta a Droga , Femenino , Tiomalato Sódico de Oro/uso terapéutico , Humanos , Inmunidad Celular , Técnicas In Vitro , Cinética , Masculino , Ratones , Persona de Mediana Edad , Embarazo , Ratas , Reproducción/efectos de los fármacos , Distribución TisularRESUMEN
Auranofin, a new oral antirheumatic gold compound, in concentrations achieved therapeutically, inhibits neutrophil phagocytosis, chemotaxis, chemiluminescence, reduction of cytochrome c, and release of lysosomal enzymes. To further characterize the mechanism by which auranofin affects neutrophils, we studied the effects of auranofin on unstimulated properties and functions of neutrophils as well as on rapidly stimulated functions. When examined by electron microscopy, 4 micrograms/ml of auranofin significantly decreased the number of visualized centriole-associated microtubules in resting cells. Furthermore, auranofin inhibited neutrophil spreading on glass and caused a decrease in negative surface charge (electrophoretic mobility). In addition, auranofin inhibited several fmet-leu-phe-stimulated responses such as shape change, increases in centriole-associated microtubules, decreases in surface charge, and elicited membrane potential changes (di-O-C5(3) dye response). Auranofin (1 micrograms/ml) inhibited fmet-leu-phe-stimulated superoxide and hydrogen peroxide production by 80% (p less than 0.05), and also increased the affinity of receptors for fmet-leu-phe (from Ka 0.035 to Ka 0.48, p less than 0.001). Auranofin also affected neutrophil responses to phorbol myristic acetate (PMA). The total amount of PMA-stimulated superoxide production was suppressed by as little as 0.4 micrograms/ml of auranofin, but the lag time for activation was shortened by low concentrations of auranofin (0.5 to 1 microgram/ml). Four micrograms per milliliter of auranofin suppressed the decrease in surface charge induced by PMA. However, auranofin did not influence superoxide production elicited by the ionophore A23187. The results indicate that auranofin affects the earliest detected responses in neutrophil activation by certain receptor-mediated stimuli.
Asunto(s)
Antiinflamatorios/farmacología , Aurotioglucosa/análogos & derivados , Quimiotaxis de Leucocito/efectos de los fármacos , Compuestos de Oro , Receptores de Superficie Celular/fisiología , Auranofina , Aurotioglucosa/metabolismo , Aurotioglucosa/farmacología , Movimiento Celular/efectos de los fármacos , Oro , Compuestos de Oro/metabolismo , Humanos , Potenciales de la Membrana/efectos de los fármacos , N-Formilmetionina Leucil-Fenilalanina/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Neutrófilos/ultraestructura , Consumo de Oxígeno/efectos de los fármacos , Receptores de Superficie Celular/efectos de los fármacos , Receptores de Formil PéptidoRESUMEN
The pharmacokinetics of gold sodium thiomalate (GST) and triethylphosphine gold (auranofin; AF) are different. Gold sodium thiomalate (GST) is completely bioavailable while only 15-25% of auranofin (AF) is absorbed. Protein binding of AF occurs to a larger extent to macroglobulins than does GST and total body retention of GST is much greater than AF at six months (30% versus approximately 1%). While terminal serum half-lives are approximately equal, total body half-lives are 250 days for GST and 69 days for AF. In addition, excretory pathways contrast markedly, with 85% of AF appearing in the feces while only 30% of GST is excreted by this route; 15% of AF gold appears in the urine and approximately 70% of GST gold is excreted via this route. With all the above differences one would expect that organ and cellular distribution of these compounds would differ. While gold from both drugs is concentrated in kidney, the percent of the dose found in the kidneys is less for AF than GST, at least in animals (0.4% vs 4.8%). Minute quantities are found in other organs but more study is needed to more clearly define organ distribution of these gold compounds, particularly in man.
Asunto(s)
Aurotioglucosa/análogos & derivados , Tiomalato Sódico de Oro/metabolismo , Oro/análogos & derivados , Absorción , Auranofina , Aurotioglucosa/sangre , Aurotioglucosa/metabolismo , Aurotioglucosa/orina , Disponibilidad Biológica , Tiomalato Sódico de Oro/sangre , Tiomalato Sódico de Oro/orina , Humanos , Cinética , Distribución TisularRESUMEN
The chemistry, pharmacology, pharmacokinetics, clinical use and efficacy, adverse effects, and dosage of auranofin, an oral chrysotherapeutic agent used in treatment of rheumatoid arthritis, are reviewed. Auranofin is lipid-soluble and is monomeric in solution. It has a modulatory effect on both the humoral and cellular immune systems. Auranofin may be a condition-dependent immunoregulating agent rather than an immunosuppressive agent. It inhibits (1) monocyte-mediated antibody-dependent cellular toxicity, (2) release of enzymes from polymorphonuclear leukocytes that may contribute to the pathogenesis of rheumatoid arthritis, and (3) neutrophil activity. In patients with rheumatoid arthritis, 15-33% of an oral dose of auranofin 6 mg is absorbed. Peak plasma gold concentrations are achieved in one to two hours. Gold is highly protein bound. Elimination occurs through the feces and urine; 73-100% of auranofin gold is excreted. Plasma half-life is three weeks. Patients receiving auranofin 3 mg twice daily for rheumatoid arthritis reported improvement after five weeks of therapy; improvement has also been reported with lower doses. Diarrhea, rashes, and pruritus were the most common adverse effects. Auranofin is safe and effective for short- and long-term treatment of patients with rheumatoid arthritis. Its relative safety and potency compared with injectable gold salts and other drugs need further study.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Aurotioglucosa/análogos & derivados , Oro/análogos & derivados , Formación de Anticuerpos/efectos de los fármacos , Auranofina , Aurotioglucosa/administración & dosificación , Aurotioglucosa/efectos adversos , Aurotioglucosa/metabolismo , Aurotioglucosa/farmacología , Aurotioglucosa/uso terapéutico , Fenómenos Químicos , Química , Humanos , Inmunidad Celular/efectos de los fármacos , Absorción Intestinal , Cinética , Educación del Paciente como Asunto , Distribución TisularRESUMEN
The ultrastructural localization of gold in resting, stimulated, and activated mouse peritoneal cells exposed in vivo and in vitro to aurothioglucose was examined by a photochemical technique. Activated macrophages from herpes simplex virus type 2 infected mice showed the heaviest accumulation of gold, located in phagolysosomes. Gold was also visualized in granules of mast cells and in nuclei of disintegrated cells. No gold was found in polymorphonuclear leucocytes and in lymphocytes. The mechanism by which gold is taken up into the cells is discussed.