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At least 19 recordsLinked to original sources
PubMed1987

Effect of aurothioglucose on glutathione and glutathione-metabolizing and related enzymes in rat liver and kidney.

The antirheumatic drug aurothioglucose is an inhibitor of the selenoenzyme GSH peroxidase. During chrysotherapy, the decreased levels of erythrocyte GSH and serum sulfhydryls of rheumatoid arthritis patients are normalized concomitant with clinical efficacy. This investigation examined the in vivo and in vitro effect of gold(I) as aurothioglucose on enzymes related to the GSH redox cycle or metabolism. The enzymes measured were GSH peroxidase, GSSG reductase, gamma-glutamyl transpeptidase, gamma-glutamylcysteine synthetase, GSH S-transferase, GSH thiotransferase, glucose-6-phosphate dehydrogenase, superoxide dismutase and catalase. Rats were injected with 30 mumol aurothioglucose/kg body wt. daily for 7 days by intramuscular injection. GSH levels in aurothioglucose-treated rats were 68% higher in erythrocytes (P less than 0.005) and 45% higher in kidney (P less than 0.001) than in control rats. Treatment with aurothioglucose did not elevate plasma or liver GSH. The enzyme activities that were changed by aurothioglucose treatment were GSH peroxidase in kidney (41% decreased, P = 0.005) and liver (13% decreased, P less than 0.05), gamma-glutamyl transpeptidase in kidney (15% decreased, P less than 0.05), and catalase in kidney (58% decreased, P less than 0.001). Kidney glucose-6-phosphate dehydrogenase activity was increased 50% (P less than 0.005) and GSH S-transferase was increased 72% (P less than 0.001). In vitro the only liver enzymes inhibited more than 50% by concentrations of less than 50 microM aurothioglucose were GSH peroxidase (50% inhibited by 25 microM aurothioglucose) and GSH thiotransferase (50% inhibited by 5 microM aurothioglucose). Studies of in vitro enzyme inhibition by aurothioglucose could not be used to predict decreased enzyme activities in vivo. Although decreased activities of two major enzymes that utilize GSH, GSH peroxidase and gamma-glutamyl transpeptidase, coincided with elevated GSH in kidneys of aurothioglucose-treated rats, a direct cause and effect relationship remains speculative.

Animals↗
PubMed2005

Parenteral gold preparations. Efficacy and safety of therapy after switching from aurothioglucose to aurothiomalate.

OBJECTIVE: For reasons of insufficient quality of the raw material, aurothioglucose was withdrawn from the Dutch market at the end of 2001. Aurothiomalate became available as an alternative preparation. We followed a cohort of patients during the first year after switching from aurothioglucose to aurothiomalate to study efficacy and tolerability. METHODS: Patients were observed at baseline and at 3 and 12 months after switching. At each visit, data on adverse drug reactions (ADR), withdrawal, and disease activity were collected. RESULTS: In total 120 patients were included [age 63(SD 15) yrs, 68% female, 93% with rheumatoid arthritis, duration of disease 15 (SD 9) years, 82% IgM rheumatoid factor-positive, with 9 (SD 9, range 0.1-45) yrs of previous aurothioglucose therapy]. Nineteen patients (16%) reported an ADR taking aurothiomalate not previously experienced with aurothioglucose, the most frequently reported being pruritus, dermatitis/stomatitis, and chrysiasis/hyperpigmentation. Twenty-nine patients (24%) withdrew from aurothiomalate within 12 months of followup for reasons of inefficacy (14%), ADR (7%), or disease in state of remission (3%). Kaplan-Meier estimates show aurothiomalate survival rates of 78.5% after 12 months. No statistically significant differences between the disease activity indicators during followup visits compared with the baseline visit were detected for the patients continuing aurothiomalate. CONCLUSION: Within the first 12 months after switching from aurothioglucose, 24% of patients withdrew from aurothiomalate. Sixteen percent of patients reported novel ADR. For the population continuing to take aurothiomalate no clinically relevant changes in disease activity were recorded after switching.

Adverse Drug Reaction Reporting Systems↗
PubMed1984

Aurothioglucose in rheumatoid arthritis. Outcome of treatment in patients intolerant of sodium aurothiomalate.

Forty-three patients in whom treatment with sodium aurothiomalate was discontinued because of adverse reactions that either were relatively severe or recurred on rechallenge received treatment with aurothioglucose in oily base. Thirty-six of them had rheumatoid arthritis, four had psoriatic arthritis and three had juvenile chronic arthritis. Aurothioglucose therapy was introduced cautiously and increased gradually to a maintenance regimen, usually 5-20 mg/week, administered by intramuscular injection. The clinical response was good in 25 patients (60%), 14 of whom continued to receive aurothioglucose therapy on a long-term basis. Adverse reactions to aurothioglucose developed in 17 patients (40%); these were generally mild, and, in all but four patients, were of the same type as those induced by sodium aurothiomalate therapy. Results show that aurothioglucose in oily base may be successfully administered in a low-dose regimen to selected patients who are intolerant of sodium aurothiomalate.

Arthritis, Rheumatoid↗
PubMed1981

Effect of aurothioglucose on liver and kidney concentrations of copper, iron, manganese and zinc.

Sixty male Swiss-Webster mice were given intraperitoneal injections of the gold-containing drug aurothioglucose in saline at 3 dose levels: 50, 200, and 400 mg/kg. Controls received i.p. injections of saline. Ten injections were administered over a 3-week period. After sacrifice, kidney and liver concentrations of gold, copper, zinc, iron, and manganese were determined by atomic absorption spectrophotometry and tissues were examined by light microscopy. Dose related increases in liver and kidney gold were found and kidney copper also increased significantly with increasing renal gold content. Kidney copper was 5.05 +/- 0.80 ppm in control animals, and 7.81 +/- 1.11 ppm, 13.01 +/- 2.49 ppm, and 17.11 +/- 4.02 ppm in mice receiving 50, 200, and 400 mg/kg aurothioglucose respectively. Renal zinc and liver zinc and copper were also significantly (P less than 0.01) increased in mice receiving the highest dose of aurothioglucose. There were no other statistically significant differences in tissue concentrations among the various groups of animals for the other liver and kidney metal concentrations determined. Tubular epithelial cells of aurothioglucose-dosed animals often had cytoplasmic vacuoles which contained granular brown-gold material; this effect was dose-related.

Animals↗
PubMed1983

Association of HLA antigens, toxic reactions and therapeutic response to auranofin and aurothioglucose in patients with rheumatoid arthritis.

To investigate the possible relation between HLA antigens and either favourable clinical response or toxic reaction to two different gold compounds, aurothioglucose and auranofin, a new orally absorbable gold compound, we studied 50 patients with rheumatoid arthritis prospectively. Of the 25 aurothioglucose-treated patients, response to treatment could not be evaluated in four patients because of early toxicity. Nine patients showed an excellent response, while 12 were moderate or non-responders. Four of the 9 excellent responders were HLA-DR3 positive, but none of the 12 moderate or non-responders possessed this antigen (P less than 0.025). In accordance with previous reports HLA-DR3 was found more frequently in patients developing toxicity on aurothioglucose than in those who did not (RR = 5.6). No association was found between HLA antigens and favourable clinical response in 25 auranofin-treated patients. Two of them showed a severe adverse reaction, neither of them being DR3-positive. HLA-DR3 positivity is associated not only with drug toxicity, but also with excellent respondership to aurothioglucose treatment.

Arthritis, Rheumatoid↗
PubMed1984

Comparison of auranofin and aurothioglucose in the treatment of rheumatoid arthritis: a single blind study.

Fifty-two patients with rheumatoid arthritis were studied in a single blind trial comparing aurothioglucose and auranofin. The duration of the study was 52 weeks. Twenty-six patients, 13 in each treatment group, dropped out during the first year of treatment. The main reason for discontinuing treatment with aurothioglucose was adverse reactions and, in the auranofin group, lack of efficacy. In those patients who continued therapy the results of treatment were comparable; patients on aurothioglucose improved slightly more than auranofin treated patients, although the difference was not statistically significant.

Adult↗
PubMed1992

Aurothioglucose inhibits induced NF-kB and AP-1 activity by acting as an IL-1 functional antagonist.

We have designed a series of recombinant CAT genes to study IL-1 signal transduction in murine fibroblast NIH 3T3 cells. We demonstrate that the HSV thymidine kinase (tk) promoter does not respond to IL-1, but that IL-1 induction of this promoter is observed after insertion of either NF-kB or AP-1 binding sites upstream of the HSV tk cap-site. We have studied the effects of indomethacin, dexamethasone and aurothioglucose (which have been used in the treatment of patients affected by rheumatoid arthritis) in the IL-1 inducible CAT assay. We show that aurothioglucose or dexamethasone is able to inhibit IL-1 induced CAT activity whereas a non-steroidal anti-inflammatory drug (indomethacin) is inactive. Order of addition experiments indicate that aurothioglucose, which has disease-modifying activity in treated patients, acts as an IL-1 functional antagonist in this system.

3T3 Cells↗
PubMed1988

Aurothioglucose effect on sulfhydryls and glutathione-metabolizing enzymes: in vivo inhibition of selenium-dependent glutathione peroxidase.

Fisher 344 rats injected with a total of 20.8 +/- 1.5 mg of gold (Au) as aurothioglucose over an 8-wk period were used to study the effect of long-term Au treatment on selenium-dependent glutathione peroxidase (SeGSHPx), other enzymes related to GSH metabolism, GSH, nonprotein sulfhydryls, and total sulfhydryls (SH) in various tissues. The indirect coupled assay for SeGSHPx revealed decreased activity in platelets of Au-treated rats but not in other tissues. Inhibition of SeGSHPx by Au is reversible upon dilution. A direct assay of GSH consumption by concentrated tissue cytosols that was developed to minimize enzyme dilution provided evidence of in vivo inhibition of SeGSHPx in kidney and liver from Au-injected rats. Kidneys of these rats had decreased (P less than 0.05) activities of GSSG reductase (36%), gamma-glutamylcysteine synthetase (19%), and gamma-glutamyl transpeptidase (26%), and increased (P less than 0.05) activities of glucose 6-phosphate dehydrogenase (90%) and GSH S-transferase (130%). The reactivity of fresh plasma SH groups with 5,5'-dithiobis-(2-nitrobenzoic acid) increased as a function of injection time. Enhanced SH reactivity suggests that Au may react with protein GSH-disulfides to release GSH. New findings were (i) decreased platelet SeGSHPx and kidney GSSG reductase in aurothioglucose-injected rats, (ii) direct in vivo inhibition of kidney and liver SeGSHPx in aurothioglucose-injected rats, and (iii) no significant correlation between the activity of GSH-metabolizing enzymes and levels of tissue GSH.

Animals↗
PubMed1976

[Gains in body composition and total fat content in mice after administration of aurothioglucose with a limited amount of animal feed].

We investigated the effect of a single application of aurothioglucose on the weight and fat content of mice in the case of a limited feed quantity. In the experiment we used 41 mice -- females of the "H" strain, of which 14 served as controls and 27 were experimental mice to which we applied aurothioglucose in the dose of 1 mg g-1 of liveweight, i. p. We found that, under the conditions of feeding a limited quantity of feeds, there occurs in the animals that had been injected with aurothioglucose a statistically significant increase of the weight gains and of the total quantity of fat compared with the control animals.

Adipose Tissue↗
PubMed2001

Hypolipidemic effect of pantothenic acid derivatives in mice with hypothalamic obesity induced by aurothioglucose.

The hypolipidemic effects of pantothenic acid derivatives (phosphopantothenate, panthenol and pantethine) were studied in mice with hypothalamic obesity. Hypothalamic obesity in mice was induced by single injection of aurothioglucose (300 mg/kg body wt, i.p.). All the tested substances were administered during the last 10 days before decapitation (i.m., of dosage equivalent to 150 mg/kg body wt of phosphopantothenate). The studied substances inhibited the weight gain of the animals with hypothalamic obesity over the last 10 days of the experiment. The treatment with aurothioglucose increased food intake and mean body weight, blood glucose level; insulin, serum total cholesterol, triglyceride, the sum of LDL + VLDL and LDL-cholesterol concentration; triglyceride and cholesterol fractions in the liver; triglyceride and FFA content as well as lipoprotein lipase activity in adipose tissue of experimental mice. The administration of the assay compounds lowered food intake and mean body weight, insulin and glucose levels and decreased the content of triglycerides, total cholesterol and cholesterol esters in serum and adipose tissue as well as raised the activity of lipoprotein lipase in adipose tissue and serum lipolytic activity in obese mice. Among the compounds studied the reverse effect of panthenol was especially pronounced. The mechanism of hypolipidemic effects of pantothenic acid derivatives can be related to the reduced resistance to insulin and activation of lipolysis in serum and adipose tissue.

Adipose Tissue↗
PubMed1975

[Studies on the number of fat cells and connective tissue cells in white adipose tissue in chronic starvation and after refeeding. I. Investigations on aurothioglucose-obese NMRI-albino-mice(author's transl)].

UNLABELLED: Former investigations (Rakow et al., 1970, 1971 b) on epididymal fat pads of lean NMRI-Albino-mice during starvation and refeeding have shown that the number of fat cells (adipocytes) remained unchanged while the number of cells o connective tissue decreased during starvation and increased during the refeeding period. In the present paper the problem has been investigated whether these variations could be demonstrated also in NMRI-albino-mice obesified by administration of aurothioglucose. MATERIAL AND METHODS: The investigations were performed with male NMRI-Albino-mice rendered obese by administration of aurothioglucose (800 mg per kg body weight). These animals were fed 2.5 g Altromin 1115 R daily for six weeks. After this they were fed Altromin 1115 R and additional oat flakes ad libitum for three (exp. groups HW3) and seven (exp. groups HW 7) days respectively. After this time the animals were sacrificed. The epididymal fat pads were removed and weighed. One of both pads of each animal was used for chemical investigations. After PCA-treatment (0.5 n, 90 degrees C. 15 min.) the DNA (Burton, 1956) and RNA (Ceriotti, 1955) was determined in the supernatant. After NaOH-treatment (0.5 n, 37 degrees C, 24 Hrs) the noncollagen protein content (Lowry et al., 1951) of the sediment was estimated. After HCl-treatment (25%, 110 degrees C, 20 hrs.) the collagen content (Stegemenn, 1958; modified by Rauskolb, 1967) was determined. The remaining fat pad was used for calculations of cell numbers in the fat cell and connective tissue cell compartment. For this reason fat cells were isolated according to Rodbell (1964). The fat cell diameters were determined microscopically and the average masses of the fat cells were estimated. From the wet weight of the fat pads and the average fat cell mass the number of fat cells was calculated. The remaining suspension of fat cells and cells of connective tissue was utilized for cell smears. These smears were stained with Schiff's reagent (Feulgen et al., 1924; Graumann, 1952). With an integrating microdensitometer (Deeley, 1955) the average relative DNA-content of single cell nuclei were measured and the ploidy patterns were estimated. From the whole DNA-content of the fat pads and the DNA-content of the fat cell population the number of cells of the connective tissue was calculated...

Adipose Tissue↗
PubMed1975

Effect of aurothioglucose on some allergic and non-allergic skin reactions in animals.

The antiphlogistic effect of aurothioglucose was examined in reversed passive Arthus reaction, delayed-type hypersensitivity and carrageenan oedema. A close association existed between the antiphlogistic effect of aurothioglucose and the pathogenetic role of polymorphonuclear leukocytes. In reversed passive Arthus reaction and in carrageenan oedema the drug decreased the inflammation considerably, whereas in delayed hypersensitivity, where the leukocytes play a less important part, it exerted only a mitigating effect.

Animals↗
PubMed1986

Low-dose aurothioglucose in pemphigus vulgaris.

Three female Jewish patients with typical pemphigus vulgaris involving the skin and the oral mucosa were managed with weekly i.m. aurothioglucose injections less than or equal to 25 mg. After obtaining a remission, the interval between injections was gradually lengthened. Fluocortolone was given in the first few weeks in decreasing dosages, starting with 60 mg/day. The two younger patients, aged 50 and 39, were in complete remission on follow-up 42 and 27 months later, respectively. They currently receive 25 mg of aurothioglucose every 6 to 8 weeks. One had had transient parotitis while on therapy. The other had had benign familial leukopenia, prior to the institution of gold therapy, and her total leukocyte and differential counts remained constant. The third patient, aged 80, who had widespread and deteriorating pemphigus, was switched to a steroid-azathioprine regimen because gold did not improve her condition quickly enough. Thus, some pemphigus patients may experience prolonged clinical remissions and improved quality of life on low doses of gold.

Adult↗
PubMed1977

[Ultrastructural study of the hypothalamic region after administration of aurothioglucose in mice].

Aurothioglucose dose of 1 mg g-1 1. w. was applied intraperitoneally to experimental female mice. After 24 hours the animals were decapitated and samples for ultrastructural examination were immediately taken from the region of the hypothalamic ventromedial nucleus. The following findings were obtained from the study of 243 electronograms of 8 experimental animals: 1. dense round particles 0.034 to 0.016 mu in size, representing the gold of aurothioglucose; 2. parenchymatous dystrophy of the mitochondria; 3. peeling off of the individual layers of myelin sheath and the granularity of these layers corresponding to the disintegration of nerve fibres.

Animals↗
PubMed1976

[Total nitrogen in mice after injections of aurothioglucose].

To mature female mice of the "H" strain aurothioglucose was applied, once in the dose of 1 mg g-1 of live weight i. p. In the case of feeding ad libitum we determined, after three months of the experiment, the nitrogen total in the fatfree dry substance. On an average the values of the total N in the animals were, after the injection of aurothioglucose, equal to those of the control animals, and the values of the nitrogen total with regard to the fatfree dry substance were practically the same.

Animals↗
PubMed1988

In vivo effects of aurothioglucose and sodium thioglucose on rat tissue sulfhydryl levels and plasma sulfhydryl reactivity.

The active component of aurothioglucose (ATG) in effecting changes in plasma sulfhydryl (SH) levels and plasma SH reactivity with 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) was determined. These two measurements are applied clinically to rheumatoid arthritis patients undergoing chrysotherapy. Normal rats were injected intramuscularly daily for seven days with 30 mumol of either ATG or sodium thioglucose (STG)/kg body wt or with an equivalent volume of the carrier, 0.05% benzyl alcohol. ATG but not STG significantly increased total SH levels in plasma, liver, and kidney. The seven-day treatment with ATG significantly increased glutathione levels in kidney but not in liver or plasma. Thus, gold(I) rather than thioglucose was the active moiety that affected SH levels in ATG-injected rats. In vivo, gold(I) was also the active moiety that stimulated plasma SH reactions with DTNB at pH 7.4, since injection of ATG but not STG stimulated the SH reactivity in fresh plasma. In vitro, ATG increased the rate of plasma reaction with DTNB at pH 7.4, thus, gold(I) ions acted as a catalyst in the SH-disulfide exchange reaction. This study demonstrates that gold(I) but not its thiol ligand strongly interacts with protein SH groups in the rat tissues. Such an interaction may play an important role in the biological actions of gold.

Albumins↗
PubMed1993

Stimulation of human neutrophil migration by aurothioglucose and thioglucose.

Migration of human neutrophils was enhanced by aurothioglucose in a concentration-dependent manner. Migration was especially pronounced when the drug was present in the lower compartment of the Boyden chamber, suggesting that the enhancement of migration was chemotactic rather than chemokinetic. Thioglucose followed the same pattern of stimulation as the related gold compound, but the enhancement at the maximally stimulating concentration was less; at higher concentrations thioglucose inhibited random migration.

Aminoquinolines↗
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↗