Excretion Of Gold Research Articles

Biodistribution, Clearance, and Toxicology of Polymeric Micelles Loaded with 0.9 or 5 nm Gold Nanoparticles.

Long-circulating gold nanoparticles (AuNPs) have garnered a great deal of interest as both imaging and therapeutic agents. However, their protracted elimination and long-term persistence within many organ systems remains a concern for clinical translation. To improve the excretion of long-circulating nanoparticles, we prepared -80 nm biodegradable polymeric micelles with 0.9 nm or 5 nm AuNPs tightly packed within the hydrophobic core. These gold-loaded polymeric micelles (GPMs) were expected to allow for improved excretion of gold, compared with single large AuNPs, owing to the smaller size and larger surface-to-volume ratio of the individual AuNPs within the micelle. Following intravenous administration of GPMs, organs were harvested and examined for gold content using inductively coupled plasma optical emission spectrometry (ICP-OES) for up to 3 months post-injection. While both GPM formulations showed significant clearance of gold over time, micelles containing 0.9 nm AuNPs showed a 72% and 67% reduction in gold content in the liver and spleen, respectively, between 1 day and 3 months post-injection, compared with a 38% and 35% reduction in mice receiving 5 nm GPMs. Furthermore, feces and urine analysis revealed approximately 7.5 and 100 times more gold, respectively, in mice that received 0.9 nm GPMs one day after injection. These findings suggest that the excretion profile of inorganic nanomaterials may be improved if clusters of small inorganic materials are used in favor of single solid particles.

Internal platinum, palladium, and gold exposure in environmentally and occupationally exposed persons

In a pilot study the urinary platinum (Pt), palladium (Pd), and gold (Au) excretion was analyzed in 27 dental technicians, 17 road construction workers and 17 school-leavers using sector field inductively coupled plasma mass spectrometry (SF-ICP-MS). Detection limits in urine were 0.24 ng/l for Pt and Au and 0.17 ng/l regarding Pd. A standardized questionnaire was used to assess information about kind and degree of contact to these metals, the physical condition of the volunteers and confounding factors. Significant differences between the three study groups were found. The mean Pt, Pd, and Au excretions of the dental technicians were significantly higher than those of the road construction workers and school-leavers. This indicates that the occupational treatment of dental alloys leads to an internal exposure to these metals which is distinctly higher than that from automobile exhaust exposure. Significant differences between Monday morning (pre-shift) and Thursday afternoon (post-shift) urine samples of the dental technicians were not found. The Pt excretion of road construction workers working near a much traveled highway was comparable with that of school-leavers being less (only environmentally) exposed to automobile exhaust. Regarding Pd and Au the road construction workers showed a tendency to higher levels in urine when compared with the school-leavers, but statistically significant differences were not found. The tendency to higher urinary Pd and Au levels in the road construction workers may be explained by their slightly greater number of noble metal containing artificial dentures, which may cause an additional exposure. A statistically significant effect of age on the urinary noble metal excretion was not detectable.

Long term urinary platinum, palladium, and gold excretion of patients after insertion of noble metal dental alloys

The aim of this study was to investigate to which extent noble-metal dental alloys contribute to the total platinum (Pt), palladium (Pd), and gold (Au) body burden of the general population. The urinary Pt, Pd, and Au excretion was determined in three non-occupationally exposed volunteers before and up to 3 months after insertion of a highgold dentalalloy. The in-vitro release of Pt, Pd, and Au from four different types of dental alloys into either artificial saliva or 1% lactic acid solution was additionally investigated. The Pt, Pd, and Au concentrations were determined by sector field inductively coupled plasma mass spectrometry (SF-ICP-MS). Before insertion of the high-gold dental alloy, the Pt excretion of the patients ranged between 1.0 and 7.4 ng l-1 (0.6-3.3 ng g-1 creatinine). In the immediate post-insertion phase the Pt excretion rose to 10.5-59.6 ng l-1 (14.5-33.2 ng g-1 creatinine). This is a mean increase by a factor of 12 compared with the average Pt excretion before insertion. Three months after insertion, the Pt excretion was still elevated by a factor of 7. Contrary to Pt, the Au and Pd excretion in urine was not significantly increased after insertion of this type of high-gold dental alloy. Our in-vitro investigations confirm the assumption that Pt, Pd, and Au are released from noble metal containing dental alloys by corrosion. Under the applied conditions, the release was in the lower ng cm-2 range. It can be concluded that the Pt release from dental alloys can predominantly contribute to the Pt exposure of non-occupationally exposed persons. It can exceed the exposure from all other environmental sources including the Pt release from automobile exhaust catalysts.

Comparative effects of chelating agents on distribution, excretin, and renal toxicity of gold sodium thiomalate in rats

The effects of various chelating agents, such as (2S)-1-(3-mercaptopropionyl)- l-proline (captopril), N-(2-mercaptopropionyl)-glycine (tipronin), l-cysteine ( l-Cys), d-cysteine ( d-Cys), N- acetyl- l-cysteine ( L-NAC), N- benzyl- d-glucamine dithiocarbamate (BGD), and ethylenendiaminetetraacetate (EDTA), on the distribution, excretion, and renal toxicity of gold sodium thiomalate (AuTM) in rats were investigated. Rats were intraperitoneally injected with the chelating agents (1.2 mmol/kg each) immediately after intravenous injection of AuTM (0.026 mmol/kg). Treatment with captopril or tiopronin significantly prevented increases in the urinary excretion of protein, aspartate aminotransferae (AST), and glucose and the blood urea nitrogen (BUN) level after AuTM injection. l-NAC and d-Cys significantly prevented increases in the urinary excretion of protein, AST, and glucose after AuTM. injection, but did not reduce to control levels. Treatment with BGD, EDTA, or l-Cys did not prevent AuTM-induced increases in the urinary excretion of protein, AST, and glucose and BUN level. Tiopronin significantly increased the urinary exretion of gold. Captopril slightly promoted both the urinary and fecal excretion of gold, resulting in the significant increase in the total excetion of the metal. Tiopronin and captopril significantly decreased the gold concentration in the kidney and liver. l-Cys, d-Cys, l-NAC, BGD, and EDTA had no significant effect on the excretion or distribution of gold at 7 days after AuTM injection. These results indicate that iopronin and captopril can ameliorate the renal toxicity induced by AuTM. In additon, the comparative effects of 2,3-dimercaptopropane sulfonate (DMPS), N-2- mercapto-2- methylpropanyl- l-cysteine (bucilamine), captopril, and tiopronin at various dose levels (1.2, 0.4 or 0.2 mmol/kg) on the distribution and renal toxicity of gold were studied. DMPS was effective in removing gold from the kidney and in protecting against the renal toxicity after AuTM injection at the even lower dose level (0.2 mmol/kg). Bucillamine and tiopronin protected against the renal toxicity of gold at dose levels of 0.4 and 1.2 mmol/kg and captopril ameliorated the gold toxicity only at higher dose level (1.2 mmol/kg).

Hepatic metabolism of colloidal gold-low-density lipoprotein complexes in the rat: evidence for bulk excretion of lysosomal contents into bile.

Rats were treated with 17 alpha-ethinyl estradiol to induce high levels of low-density lipoprotein receptors in hepatocytes. When these rats were given intravenous injections of low-density lipoprotein-colloidal gold complexes, most of the gold (labeled with 195Au) appeared to be taken up by Kupffer cells, as were complexes of colloidal gold with albumin or polyvinylpyrrolidone. However, when these rats were also administered gadolinium chloride, which blocks Kupffer cell activity, most of the low-density lipoprotein-gold (but not gold complexed with albumin or polyvinylpyrrolidone) was taken up into hepatocytes by receptor-mediated endocytosis and concentrated in peribiliary lysosomes, as determined by electron microscopy. Colloidal gold taken up as a complex with low-density lipoprotein was excreted into the feces via the common bile duct at a maximal rate of about 5% daily, 4 to 12 days after injection. Thereafter, the rate of gold excretion fell off until reaching a plateau after 3 weeks. At this late time, most of the colloidal gold was shown by electron microscopy to be in Kupffer cells, whereas earlier (6 days after injection) it was contained mainly in older hepatocytic lysosomes, identified by lipofuscin granules. It is concluded that, in rats, hepatocytic lysosomes empty most of their contents into bile every week or two, apparently by exocytosis.

Patterns of urinary excretion of gold in patients with rheumatoid arthritis undergoing chrysotherapy.

Thirty patients receiving gold therapy for rheumatoid arthritis (RA) were studied for the urinary excretion of gold. Statistical analysis of all the urine specimens passed over a period of four days by each patient showed that a definite rhythm of gold excretion exists for each patient which is possibly related to water excretion but not to creatinine excretion. The study indicates possible reasons for the inability of earlier workers to relate gold excretion to the general body gold status of patients and suggests that as the study of 24 hour excretions of gold may be an insensitive marker of gold excretion, closer examination of individual patient rhythms of gold excretion could possibly provide a more useful method of analysis.

Patterns of gold levels in urine, serum, and saliva in patients with rheumatoid arthritis undergoing chrysotherapy.

Twenty patients undergoing treatment with aurothiomalate for rheumatoid arthritis (RA) were studied for the presence of gold in all urine specimens passed over four days and for gold in the serum of blood drawn by venous section at 10.00, 16.00, and 22.00 hours on a single day of the study. Specimens of saliva collected at the same times as the blood specimens were also analysed for (total) gold content. Eighteen patients showed rhythmic urinary gold excretion. Variations were observed in the serum levels for total, free, and protein bound gold at different times of the day and night together with similar variations in the salivary total gold levels. It was established that a possible relation exists between urinary gold, serum gold, and salivary gold such that at times of higher urinary gold excretion the serum gold levels (total, free, and protein bound) and the total salivary gold levels were decreased. Conversely, at times of lower urinary gold excretion serum and salivary gold levels were increased.

Excretion of gold into human breast milk.

After the administration of 70 mg and 50 mg aurothiomalate, respectively, to 2 patients with rheumatoid arthritis, significant amounts of gold appeared in breast milk.

Tissue disposition and excretion of gold and 14C in rats treated with sodium aurothio[1,4-14C]malate or thio [1,4-14C] malic acid.

In rats injected intramuscularly with sodium aurothio[1,4-14C]malate, 80% of the 14C was excreted in the urine, mostly in 24 h, 2% in the faeces and 10% as 14CO2 in the expired air during the first six hours with none thereafter. Urinary and faecal gold represented 5% and 2.5% of the dose, respectively. In rats given thio[1,4-14C]malic acid, 50% of the 14C was excreted in the urine, 10% in the expired air as 14CO2 and 2% in the faeces. Radioactivity was found in all tissues with distribution similar for the two compounds, the major sites of accumulation being bone, kidney and liver. Significantly higher amounts of 14C were found in the 14C-aurothiomalate-dosed animals, notably in bone and kidney. Gold was located principally in kidney, liver, lung and spleen with smaller amounts elsewhere. At least seven radioactive metabolites (including sodium aurothiomalate and thiomalic acid) were present in the urine of rats given 14C-aurothiomalate. Urine from 14C-thiomalic acid-treated rats contained at least five radiolabelled compounds, one of which was thiomalic acid. Results show that most of the gold was removed from the thiomalate moiety, however, the 14C distribution and the radioactive metabolites in urine demonstrated that some intact aurothiomalate remains.

Effect of penicillamine on blood levels and urinary excretion of gold.

Effect of penicillamine on blood levels and urinary excretion of gold.

The effect of penicillamine and 2,3-dimercaptosuccinic acid on urinary excretion and tissue distribution of gold.

In order to study interactions in vivo between Au+ and SH-containing agents, groups of mice were given 35 mumol/kg of radiolabelled [195Au] thiomalate (Myocrisin) intramuscularly. The administration of Myocrisin is known to result in protein-bound gold and free thiomalate (mercaptosuccinate). High doses of dimercaptosuccinate (1 mmol/kg daily) increased the urinary excretion of radiolabelled gold [195Au] for several days. Treatment for 7 days with 1 mmol/kg of penicillamine or dimercaptosuccinate reduced the blood and kidney levels of gold to 30--50% of the controls. The oral administration of penicillamine in high doses, 1--10 mmol/kg, increased significantly the urinary excretion of [195Au] the first day after the Myocrisin injection, but on the subsequent days the radio-metal excretion was unaffected by the treatment. A lower dose level of penicillamine (0.3 mmol/kg daily) gave rise to only a small and insignificant increase in the urinary excretion of gold. The present results indicate that penicillamine at low clinical doses is an inefficient chelator of gold, while high doses (presumably comparable to about 1 200 mg daily in humans) may mobilize certain amounts of the metal deposits.

Treatment of rheumatoid arthritis with penicillamine

ENICILLAMINE is an active drug useful in the treatment of RA, but in some patients its use is associated with potentially hazardous adverse effects, in particular thrombocytopenia, some rashes, and proteinuria. It is a drug with much to offer, but our understanding of its place in the long-term treatment of RA is still in its infancy. Clinical problems are discussed in the light of personal experience with 109 patients observed for up to 3 yr-this group includes a yearlong two-dose comparative study. Indications for treatment, dosage, and management (including monthly mandatory urinanalysis and hematologic checks) are discussed. PHARMACOLOGY Penicillamine is &@dimethylcysteine-a sulphur-containing amino acid. It exists in the D or L form, the latter being considerably more toxic. It is invariably prescribed as D-penicillamine (DPA). Studies with3” S-labeled DL-penicillamine of synthetic manufacture in patients with Wilson’s diseaseI showed that absorption was rapid, with a peak blood level 1 hr after ingestion, followed by a rapid fall, although there were detectable amounts in the plasma at 48 hr. D-penicillamine is oxidized by the cytochrome system of the body and is then excreted as the disulphide. Pharmacologically, DPA is a very versatile drug (Table 1). In Wilson’s disease it forms stable chelates with copper and is the drug of choice in this otherwise invariably fatal condition. DPA forms similar chelates with other heavy metals and is successfully established as treatment for heavy metal poisoning. This led to its use in patients with RA who developed a toxic reaction to chrysotherapy, but in 1975 Jessop”’ found no evidence of increased urinary gold excretion and concluded that DPA is unlikely to be useful in the management of patients with gold toxicity. In cystinuria DPA forms mixed disulphides with cystine and cysteine, the solubility of the former being greatly increased, hence decreasing the risk of stone formation.4” The rationale for the use of DPA in active scleroderma is based on experimental and in vivo evidence which shows that DPA interferes with the formation of cross-links between tropocollagen molecules and cleaves them when newly formed.20’36 We are uncertain how DPA affects the course of RA, but its potential use stems from Jaffe’s observation 28 that DPA dissociated macroglobulins (rheumatoid factor) in the synovial fluid after intra-articular injection. From here pharmacology progressed to clinical use. The story is worth reporting in detail. HISTORICAL

The urinary excretion of trace elements before and during treatment with hydralazine.

Urinary excretion of antimony, arsenic, bromine, cadmium, caesium, cobalt, copper, gold, iron, mercury, molybdenum, ribidium, scandium, selenium, silver, tungsten and zinc from five hypertensive patients beforeand during treatment with hydralazine has been investigated. The method consisted of neutron activation analysis combined with a recently developed ion exchangee technique. The mean copper excretion during treatment with hydralazine was found to be more than twice that before treatment.

Blood and urine gold levels during chrysotherapy for rheumatoid arthritis.

In this study the value of undertaking routine blood and urine estimations was assessed in relation to achieving maximum efficacy and safety in chrysotherapy. It was found that a favourable response to gold was forthcoming in approximately two-thirds of patients and occurred irrespective of the patients' disease duration or severity, or the mean serum gold level or the mean urinary gold excretion, estimated immediately before the next gold injection was due. The presence of rheumatoid nodules and the patients' advancing age were associated with a less favourable clinical response to gold. Those patients who derived a marked benefit from chrysotherapy did so significantly earlier in their course than those who derived only moderate benefit. A frequent correlation was seen in individual patients between serum gold levels and urinary gold excretion. This was most marked in those patients showing a favourable response to gold.

Pharmacodynamics of 197Au and 195Au labeled aurothiomalate in blood. Correlation with course of rheumatoid arthritis, gold toxicity and gold excretion.

AbstractThe relationships between serum stable gold (197Au) concentration and serum and whole blood radioactive gold (195Au) disappearance curves to clinical course and gold excretion are analyzed in this prospective clinical‐metabolic study of 18 patients with active rheumatoid arthritis (RA). Patients received a standard course of Myochrysine (197Au aurothiomalate), were given 195Au labeled aurothiomalate to monitor current dose dynamics, and clinically evaluated at regular intervals. Stable and radiogold concentrations in blood were measured serially on an outpatient basis and during periods of hospitalization using neutron activation anallysis and standard radiometric techniques. Serum concentrations of both isotopes failed to correlate with clinical course and toxicity. Serum radiogold disappearance curves were similar in patients who received radioactive gold on two or more occasions, despite changes in clinical course. Whole blood radiogold disappearance curves however were significantly different in most and least improved patients. These findings, and others reported herein, suggest that a) the probable interstitial or intracellular mechanism(s) of action of gold on the inflammatory process are not dependent upon serum gold concentrations and b) they raise the possibility that whole blood radiogold disappearance curves would provide a means of selecting those patients who will derive maximum therapeutic benefit from chrysotherapy.

Trace elements in serum and urine from hypertensive patients treated for six months with chlorthalidone.

Abstract. Urinary excretion and serum concentration of antimony, arsenic, bromine, cadmium, caesium, cobalt, copper, gold, iron, mercury, molybdenum, rubidium, scandium, silver, tungsten and zinc from 6 hypertensive patients before and after 6 months' treatment with chlorthalidone have been investigated. The method consisted in neutron activation analysis combined with a recently developed ion exchange technique. A previously observed increase in urinary excretion of bromine, cadmium, cobalt, rubidium and zinc after short‐term treatment with chlorthalidone was also present after long‐term treatment with regard to rubidium and zinc and possibly also to bromine, cadmium and cobalt. A significantly lowered concentration in serum after long‐term treatment was found only for rubidium.

Trace elements in serum and urine from hypertensive patients before and during treatment with chlorthalidone.

Abstract. Urinary excretion of antimony, arsenic, bromine, cadmium, caesium, cobalt, copper, gold, iron, mercury, molybdenum, rubidium, scandium, silver, tungsten and zinc from 16 hypertensive patients before and during treatment with chlorthalidone has been investigated. The serum concentration of these elements before and after treatment was determined in 10 of the patients. The method consisted of neutron activation analysis combined with a recently developed ion exchange technique. The serum concentration as well as the urinary excretion of the 17 trace elements investigated in untreated hypertensive patients did not differ significantly from those of normotensive subjects. During treatment with chlorthalidone a raised urinary excretion of bromine, cadmium, cobalt, rubidium and zinc and a decreased urinary excretion of caesium were observed. A significantly decreased serum concentration after 5 days' treatment was only noted for rubidium.

Plasma levels and urinary excretion of gold during routine treatment of rheumatoid arthritis.

Plasma levels and urinary excretion of gold during routine treatment of rheumatoid arthritis.

D-penicillamine for the treatment of gold dermatitis

D-penicillamine was effective in the treatment of a case of persistent gold dermatitis. Clinical improvement occurred after the administration of 1 gm. of penicillamine daily for seven days. Increased urinary gold excretion, fecal gold excretion and plasma gold levels were demonstrated by neutron activation analysis. Although d-penicillamine is effective in the treatment of gold toxicity, its use should be reserved for chronic toxicity which has not responded to more conservative methods.

Influence of chelation on gold metabolism in rats.

SummaryThermal neutron activation has been applied to the analysis of gold in biological samples. A convenient procedure is described for measurement of gold with a standard deviation of ± 5% in the range of 0.05 to 40.0 μg/ml. The tissue distribution and excretion of gold injected in rats is dependent upon the nature of the gold carrier. Mobilization of preinjected gold by various agents may enhance excretion but causes simultaneous redistribution of the metal in tissues. D,L-penicillamme, the most effective of a group of -SH containing gold binding compounds studied, decreased the gold content of spleen and lung but caused an increased gold deposition in liver and kidney during mobilization of predeposited tissue gold.