Localized chrysiasis, aluminum salt deposition and dystrophic calcification a decade after gold injections.

Localized chrysiasis is rare and can occur in two settings: after localized or traumatic implantation of elemental gold or gold salts or after localized laser or light therapy in someone who has been previously exposed to systemic gold therapy. We report a unique case of localized chrysiasis with associated aluminum salt deposition and sclerosing lipogranulomas because of previous injections of aurothioglucose (Solganal®). The unique histopathologic findings seen in this case have not been previously reported.

A novel and comprehensive mouse model of human non-alcoholic steatohepatitis with the full range of dysmetabolic and histological abnormalities induced by gold thioglucose and a high-fat diet.

BACKGROUND: The search for effective treatments of non-alcoholic steatohepatitis (NASH), now the most common chronic liver disease in affluent countries, is hindered by a lack of animal models having the range of anthropometric and pathophysiological features as human NASH. AIMS: To examine if mice treated with gold thioglucose (GTG) - known to induce lesions in the ventromedial hypothalamus, leading to hyperphagia and obesity - and then fed a high-fat diet (HF) had a comprehensive histological and dysmetabolic phenotype resembling human NASH. METHODS: C57BL/6 mice were injected intraperitoneally with GTG and then fed HF for 12 weeks (GTG+HF). The extent of abdominal adiposity was assayed by CT scanning. A glucose tolerance test and an insulin tolerance test were performed to evaluate insulin resistance (IR). Histological, molecular and biochemical analyses were also performed. RESULTS: Gold thioglucose+HF induced dysmetabolism, with hyperphagia, obesity with increased abdominal adiposity, IR and consequent steatohepatitis, with hepatocyte ballooning, Mallory-Denk bodies, perivenular and pericellular fibrosis as seen in adult NASH, paralleled by an increased expression of the profibrogenic factors, transforming growth factor-ß1 and TIMP-1. Plasma adiponectin and the expression of adiponectin receptor 1 and receptor 2 were decreased, while PPAR-γ and FAS were increased in the livers of GTG+HF mice. In addition, GTG+HF mice showed glucose intolerance and severe IR. CONCLUSIONS: Treatment with GTG and HF diet induce, in mice, a comprehensive model of human NASH, with the full range of dysmetabolic and histological abnormalities.

Fatal gastric distension in a gold thioglucose mouse model of obesity.

This case report addresses the problem of underreporting negative results and adverse side effects in animal testing. We present our findings regarding a hyperphagic mouse model associated with unforeseen high mortality. The results outline the necessity of reporting detailed information in the literature to avoid duplication. Obese mouse models are essential in the study of obesity, metabolic syndrome and diabetes mellitus. An experimental model of obesity can be induced by the administration of gold thioglucose (GTG). After transcending the blood-brain barrier, the GTG molecule interacts with regions of the ventromedial hypothalamus, thereby primarily targeting glucose-sensitive neurons. When these neurons are impaired, mice become insensitive to the satiety effects of glucose and develop hyperphagia. In a pilot study for optimising dosage and body weight development, C57BL/6 mice were treated with GTG (0.5 mg/g body weight) or saline, respectively. Animals were provided a physiological amount of standard diet (5 g per animal) for the first 24 hours after treatment to prevent gastric dilatation. Within 24 hours after GTG injection, all GTG-treated animals died of gastric overload and subsequent circulatory shock. Animals developed severe attacks of hyperphagia, and as the amount of provided chow was restricted, mice exhibited unforeseen pica and ingested bedding material. These observations strongly suggest that restricted feeding is contraindicated concerning GTG application. Presumably, the impulse of excessive food intake was a strong driving force. Therefore, the actual degree of suffering in the GTG-induced model of hyperphagia should be revised from moderate to severe.

Increased radiotoxicity in two cancerous cell lines irradiated by low and high energy photons in the presence of thio-glucose bound gold nanoparticles.

PURPOSE: Gold nanoparticles modified by thio-glucose are believed to increase the toxicity of radiotherapy in human malignant cells. We report the effect of thio-glucose bound gold nanoparticles (Glu-G nanoparticles), 16 nm in size, on two human lung (QU-DB) and breast (MCF7) cancer cell lines combined with kilo and megavoltage X-rays. MATERIALS AND METHODS: The shape and surface characteristics, the size distribution and light absorption spectrum of the prepared nanoparticles were measured by transmission electron microscopy, dynamic light scattering, and ultraviolet-visible spectrophotometry, respectively. The cell uptake was assayed using the atomic absorption spectrometry. Mitochondrial activity, colony formation, and comet assays were applied to assess and compare the enhanced radiotoxicity of 100 KV and 6 MV X-rays, when combined with Glu-G nanoparticles. RESULTS: Glu-G nanoparticles had no significant toxicity for MCF7 and QU-DB cells up to 100 micromolar concentration. Compared to radiation alone, the intracellular uptake of Glu-G nanoparticles resulted in increased inhibition of cell proliferation by 64.1% and 38.7% for MCF7 cells, and 64.4% and 32.4% for QU-DB cells by 100 kVp and 6 MV X-rays, respectively. Comet assay confirmed an increase of DNA damage as a result of combination of 6 MV photons with Glu-G nanoparticles. CONCLUSION: Glu-G nanoparticles have remarkable potential for enhancing radiotoxicity of both low and high energy photons in MCF7 and QU-DB cells.

Differential response of arcuate proopiomelanocortin- and neuropeptide Y-containing neurons to the lesion produced by gold thioglucose administration.

The effect of gold thioglucose (GTG) administration on neurons containing feeding-related peptides in the hypothalamic arcuate nucleus was examined in mice. Intraperitoneal GTG injection increased the body weight and produced a hypothalamic lesion that extended from the ventral part of the ventromedial nucleus to the dorsal part of the arcuate nucleus. Neurons containing proopiomelanocortin (POMC) and neuropeptide Y (NPY) present in the dorsal part of the arcuate nucleus were destroyed by GTG. In addition, the peptide-containing fibers that extended from the remaining arcuate neurons were degenerated at the lesion site. The number of POMC-containing fibers in the paraventricular nucleus, dorsomedial nucleus, and lateral hypothalamus was found to have decreased significantly when examined at 2 days and 2 weeks after the GTG treatment. In contrast, the number of NPY-containing fibers in the lateral hypothalamus remained unchanged after the GTG treatment, probably because of the presence of an unaffected NPY-containing fiber pathway passing through the tuberal region and projecting onto the lateral hypothalamus. The number of NPY-immunoreactive fibers in the paraventricular and dorsomedial nuclei showed a moderate but significant decrease at 2 days after the GTG treatment, but it recovered to the normal levels 2 weeks later. The NPY-containing fibers were found to have regenerated across the lesion site 2 weeks later, and this might contribute to the recovery of the NPY-immunoreactive fibers in these regions. The present results first demonstrate that POMC- and NPY-containing neurons in the arcuate nucleus respond differently to the lesion produced by the GTG treatment.

Beneficial effects of Zingiber officinale on goldthioglucose induced obesity.

Goldthioglucose induces in mice a significant increase in body weight, glucose, insulin and lipid levels. Treatment with 250 mg/kg of methanol and ethyl acetate extracts of Zingiber officinale for 8 weeks produces significant reduction in body weight, glucose, insulin and lipid levels as compared to obese control mice. The reduction in elevated glucose along with elevated insulin levels indicates that the treatment with Z. officinale improves insulin sensitivity.

Selenium supplementation acting through the induction of thioredoxin reductase and glutathione peroxidase protects the human endothelial cell line EAhy926 from damage by lipid hydroperoxides.

The human endothelial cell line EAhy926 was used to determine the importance of selenium in preventing oxidative damage induced by tert-butyl hydroperoxide (tert-BuOOH) or oxidised low density lipoprotein (LDLox). In cells grown in a low selenium medium, tert-BuOOH and LDLox killed cells in a dose-dependent manner. At 555 mg/l LDLox or 300 microM tert-BuOOH, >80% of cells were killed after 20 h. No significant cell kill was achieved by these agents if cells were pre-incubated for 48 h with 40 nM sodium selenite, a concentration that maximally induced the activities of cytoplasmic glutathione peroxidase (cyGPX; 5.1-fold), phospholipid hydroperoxide glutathione peroxidase (PHGPX;1.9-fold) and thioredoxin reductase (TR; 3.1-fold). Selenium-deficient cells pre-treated with 1 microM gold thioglucose (GTG) (a concentration that inhibited 25% of TR activity but had no inhibitory effect on cyGPX or PHGPX activity) were significantly (P<0.05) more susceptible to tert-BuOOH toxicity (LC(50) 110 microM) than selenium-deficient cells (LC(50) 175 microM). This was also the case for LDLox. In contrast, cells pre-treated with 40 nM selenite prior to exposure to GTG were significantly more resistant to damage from tert-BuOOH and LDLox than Se-deficient cells. Treatment with GTG or selenite had no significant effect on intracellular total glutathione concentrations. These results suggest that selenium supplementation, acting through induction of TR and GPX, has the potential to protect the human endothelium from oxidative damage.

Auranofin versus injectable gold. Comparison of pharmacokinetic properties.

The new oral gold compound auranofin differs pharmacokinetically from the existing injectable gold compounds such as gold sodium thiomalate. Following a standard 50 mg intramuscular injection of gold sodium thiomalate, plasma gold levels rise sharply, peak between 400 and 800 micrograms/dl in approximately two hours, then decline to approximately 300 micrograms/dl by seven days. With repeated 50 mg weekly injections, stable plasma concentrations are gradually achieved, although absolute levels vary greatly among individual subjects. On the other hand, auranofin is associated with lower (50 to 70 micrograms/dl) and more predictable plasma concentrations. Single-dose kinetic studies using isotopically labelled gold show that the plasma disappearance half-time for gold sodium thiomalate is relatively rapid (approximately six days) compared with 17 days for auranofin. Both compounds are retained within the body over prolonged periods. Retention of auranofin is much less, about 1 percent of the original tracer dose remaining at 180 days, compared with more than 30 percent retention of gold sodium thiomalate. Excretory pathways are notable different. The majority of gold sodium thiomalate (greater than 70 percent) is excreted by the kidneys, with the remaining fraction appearing erratically in the stool. In contrast, the enteric pathway represents the major excretory route for auranofin, with nearly 85 percent of the dose eventually recoverable in the stool and less than 15 percent in the urine. In human subjects, parenterally administered gold is almost universally dispersed among body tissues, although highest concentrations occur in the organs of the reticuloendothelial system and the adrenal and renal cortices. Comparable studies are not available for auranofin, but animal studies show comparatively less affinity for liver, kidney, and spleen. To date, attempts to correlate the pharmacokinetics of the injectable gold compounds with clinical response and toxicity have been largely unsuccessful. The distinctive pharmacokinetic profile of auranofin, when compared with gold sodium thiomalate, may nonetheless account in part for the clinical and pharmacologic differences between these compounds.

Auranofin: dose-related risk to benefit.

Two separate, double-blind studies examined the most appropriate starting dose of auranofin, an orally administered gold compound, for the management of rheumatoid arthritis. One study indicated that neither of the two tested doses, 1 or 9 mg auranofin daily, was ideal; the 1 mg dose was insufficient therapeutically, whereas the 9 mg dose was associated with frequent lower gastrointestinal side effects. In the other study, which compared 2 and 6 mg auranofin daily, both doses resulted in similar clinical improvement and untoward effects, although the higher dose had greater efficacy sooner. Thus, it appears that 6 mg auranofin daily is the most appropriate starting dose.

Clinical pharmacokinetics of oral and injectable gold compounds.

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.

Optimum Management of juvenile chronic polyarthritis.

The early diagnosis of juvenile chronic polyarthritis rests on the recognition of 3 district modes of onset that are important in preventing deformities, blindness, and even death. Systemic onset is characterised by typical systemic features, including high spiking fever and rheumatoid rash; polyarticular onset is characterised by arthritis of more than 4 joints; and pauciarticular onset by involvement of 4 joints or less, most often a knee initially. Management must be individualised, including the use of non-steroidal anti-inflammatory drugs of which aspirin remains the drug of choice. The course of progressive polyarthritis, found in 15% of children, necessitates the additional use of slow-acting agents, such as intramuscular gold. Supportive measures include rest, splinting and exercise. Regular slit-lamp examination is mandatory to screen for asymptomatic iridocyclitis, which if undetected and untreated may result in blindness.

Lesions of glucose-responsive neurons impair synchronizing effects of calorie restriction in mice.

Calorie restriction can induce phase-advances of daily rhythms in rodents exposed to light-dark cycles. To test whether glucose-responsive neurons are involved in the synchronizing effects of calorie restriction, C57BL/6J mice were injected with gold-thioglucose (GTG; 0.6 g/kg) which damages glucose-responsive neurons, primarily located in the ventromedial hypothalamus. From the day of injection, GTG-treated and control mice received a hypocaloric diet (66% of ad libitum food intake) 2 h after lights on. When mice were transferred to constant darkness after 4 weeks and fed ad libitum, the onset of circadian rhythm of locomotor activity was phase-advanced by 1 h in control but not in GTG-treated mice. Therefore, glucose-responsive neurons in the ventromedial hypothalamus may play a role in the synchronizing effects of calorie restriction on circadian rhythmicity.

Management of pemphigus with gold compounds: a long-term follow-up report.

Fourteen of 15 patients with pemphlgus have responded successfully to systemically administered gold therapy for up to four years. Eight of the 15 (56%) are in remission, requiring no therapy (mean, 21 months). The remaining seven patients are receiving maintenance systemic gold therapy. Only one instance of toxicity was seen during maintenance therapy. The high remission rate associated with gold therapy and the infrequent side-effects during maintenance therapy suggest that systemically given gold therapy may be the treatment of choice for the management of pemphigus, following initial therapy with corticosteroids when necessary.

Energy balances in obese mice.

According to most existing theories, the regulation of energy balance is achieved by control of energy intake. This study was undertaken to find out whether there was control of energy output as well. Food intake, energy balance and the feed efficiency of weanling female mice made obese with injections of gold-thioglucose and monosodium glutamate indicate that the obesity is primarly due to an increased energetic efficiency, and suggest that the hypothalamus plays a role in controlling energy output. In the case of treatment with MSG, a relative obesity was observed, i.e. an increase in body fat without any change in body weight. This indicates that the CNS centres for the regulation of body weight and body fat are probably not the same. It is suggested that MSG obesity will be a suitable model for comparative studies of body weight and the regulation of fat content. It is concluded that chemically induced obesity is due more to a lower metabolic rate than to an elevated food intake.

Subchronic treatment of rats with aurothioglucose; effects on plasma, hepatic, renal and urinary zinc, copper and metallothionein.

Administration of sodium aurothioglucose (10 mg/kg per day) to female rats for up to 8 weeks resulted in no apparent effects on the kidney. Gold accumulated in kidney, liver, spleen, pancreas, skin and blood. Although plasma and hepatic gold levels increased with time, no remarkable change in either copper, zinc or metallothionein (MT) levels was observed. Gel filtration chromatography of plasma showed binding of gold to albumin, whereas copper was associated with albumin, ceruloplasmin and a protein eluting in the void volume of the Sephadex G-150 column. Almost all of the hepatic gold was bound to proteins other than MT. In the kidney, not only gold but also copper and MT increased rapidly, reached a maximum between 2 and 4 weeks and exhibited insignificant change thereafter. Gold-treated animals showed an increase in binding of copper to the very high molecular weight plasma protein, which may be involved in transport of copper to the kidneys. Urinary gold and MT followed a pattern similar to that in the kidney. Renal zinc also increased but returned to normal by week 8. In renal cytosol 57% and 54% of the gold and copper, respectively, were associated with MT. It appears that the elevated levels of copper and zinc, rather than gold, are responsible for the induction of MT synthesis. This then provides a mechanism by which gold and the inducing metals are retained by the kidney.

Non-steroidal anti-inflammatory drugs in combination. Experimental observations.

Diflunisal in combinations with oxaprozin, indomethacin and sodium meclofenamate produced significant synergistic suppression of carrageenan-induced oedema of the rat foot-pad. Oxaprozin, benoxaprofen, indomethacin, diflunisal, sodium meclofenamate and auranofin in some paired combinations but not in others were associated with a greater effect than the component drugs used alone. Antagonism was demonstrated with other combinations of these drugs.

Triethylphosphine gold: cellular uptake and disposition after single and repeated oral doses in rats.

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.

Aurothioglucose overdosage in five patients with rheumatoid arthritis.

Five patients with active seronegative, rheumatoid arthritis, HLA-DR3 negative, received inadvertently 250 to 500 mg of aurothioglucose instead of their usual weekly dose, during standard remission-inducing chrysotherapy. Subsequently a rapid and sustained clinical remission appeared in all five patients.

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.