HeLa cell survival is affected by goldthioglucose (0-100 μM, 24-72 h), which suppresses TrxR1 activity in the cytoplasm of the cells [1]. For six hours, goldthioglucose (0–30 μM) had no effect on the cells. Extremely low goldthioglucose (0–20 μM, 24 h) demonstrated remarkable synergy with Ebselen, resulting in the oxidation of Trx1 (thioredoxin 1), the build-up of reactive oxygen species (ROS), and cell death [1]. In OM10.1 and Ach2 cells, goldthioglucose (0-100 μM, 3–12 days) suppresses p24 levels and prevents HIV-1 replication [2]. A dose-dependent cell survival experiment using autioglucose (0-25 μM, 12 days) [1]

In a therapeutically relevant mouse model of ARDS, auurothioglucose (25 mg/kg, ip, single dose) dramatically decreased lung injury and recurrence rates. GSH is necessary for aurothioglucose to have a protective effect[3]. i.p., single-dose, 300 mg/kg gold thioglucose

Cell Viability Assay[1]
Cell Types: HeLa cells
Tested Concentrations: 0, 5, 10, 50, 100 μM
Incubation Duration: 24, 48, 72 h
Experimental Results: Percentage of TrxR activity inhibited by more than 90 in HeLa cells at 100 μM. Even after 72 hrs (hours), cell viability was not affected by ATG treatment at a concentration of 100 μM.

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Western Blot Analysis[1]
Cell Types: HeLa cells
Tested Concentrations: 0, 5, 10 and 100 μM
Incubation Duration: 24 hrs (hours)
Experimental Results: There was no significant oxidation of Trx1 or Trx2 in HeLa cells.

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Western Blot Analysis[2]
Cell Types: OM10.1, Ach2 Cell
Tested Concentrations: 0, 4, 10, 25 and 100 μM
Incubation Duration: 3, 6 or 12 days
Experimental Results: Significant inhibition of p24 levels. After 12 days of incubation, the viability of cells treated with 10, 25, and 100 μM Aurothioglucose diminished to 60% of the control.

Animal/Disease Models: Adult male C3H/HeN mice (8-12 weeks, LPS/hyperoxia exposed mice, inflammation/hyperoxia ARDS model) [3]
Doses: 25 mg/kg
Route of Administration: ) Induces hypothalamic scientific research [4]. Intratracheal LPS administration was administered intraperitoneally (ip) (ip) 12 hrs (hrs (hours)) later, and the results of a single dose were: lung injury was Dramatically diminished, lung GCLM expression and GSH levels were increased, and mortality was diminished.

Absorption, Distribution and Excretion
In general, aurothioglucose is administered via intramuscular injection - preferably intragluteally - after which the resultant absorption is typically slow and erratic. Gold is absorbed from injection sites, reaching peak concentration in blood in about 4 to 6 hours. After a single intramuscular injection of 50 mg of aurothioglucose suspension in two subjects, peak serum levels were observed at approximately 235 g/dL and 450 g/dL. Storage of gold in human tissues depends upon organ mass as well as the concentration of gold.Subsequently, tissues having the highest gold levels (w/w) may not necessarily have the largest total amounts of gold. The highest concentrations of gold are generally found in the lymph nodes, adrenal glands, liver, kidneys, bone marrow, and spleen. Relatively small concentrations are actually found in the articular structures. In particular, following the administration of aurothioglucose doses, about 85% of the resultant plasma gold will be stored in the major bodily gold depots, which in decreasing order of total gold content are, the lymph nodes, bone marrow, liver, skin, and bone.
Following a single intramuscular injection of 50 mg aurothioglucose in each of two patients, one study determined that approximately 70% of the agent is eliminated in the urine and 30% in the faeces. In general, excretion is primarily in the urine.
Readily accessible data regarding the volume of distribution of aurothioglucose is not available.
When a standard weekly treatment schedule of aurothioglucose administrations is followed, about 40% of the given dose is excreted each week, while the remainder is excreted over a longer period.
The true potential of gold compounds, including ... aurothioglucose, to cumumulate has not been clearly defined, but it is clear that substantially larger amounts of gold are retained in the body during therapy with parenteral gold compounds than during therapy with auranofin.
Small amounts of gold have been shown to be distributed into milk in women receiving aurothioglucose ... .
Gold is absorbed from injection sites, reaching peak concentration in blood in four to six hours. Following single intramuscular injection of 50 mg Solganal /aurothioglucose/ suspension in each of two patients, peak serum levels were about 235 mcg/dl in one patient and 450 mcg/dl in the other. In plasma, 95% is bound to albumin fraction. Approximately 70% of the gold is eliminated in the urine and approximately 30% in the feces. When a standard weekly treatment schedule is followed, approximately 40% of the administered dose is excreted each week, and the remainder is excreted over a longer period.
After the initial injection, the serum level of gold rises sharply and declines over the next week. Peak levels with aqueous preparations are higher and decline faster than those with oily preparations. Weekly administration produces a continuous rise in the basal value for several months, after which the serum level becomes relatively stable. After a standard weekly dose, considerable individual variation in the levels of gold has been found. A steady decline in gold levels occurs when the interval between injections is lengthened, and small amounts may be found in the serum for months after discontinuance of therapy. The incidence of toxic reactions is apparently unrelated to the cumulative body content of gold.
For more Absorption, Distribution and Excretion (Complete) data for AUROTHIOGLUCOSE (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
Although the exact metabolic fate of aurothioglucose is not formally understood, the principal gold species that can be found in the urine and blood of a patient following the administration of the drug is [Au(CN)2]-.
For a patient receiving gold sodium thiomalate the principal gold species in the urine is [Au(CN)2]-, which is also seen in a low molecular weight infiltrate of the blood. The same compound is also identified in the urine and blood of a patient taking solganol

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Biological Half-Life
The biological half-life of gold salts (like aurothioglucose) following a single 50 mg dose demonstrates a biological half-life of about 3-27 days, where the half-life seemingly increases with increased number of doses. Following successive weekly doses, the half-life increases and may become 14-40 days after the third dose and up to 168 days after the eleventh weekly dose.
The biological half-life of gold salts following a single 50 mg dose has been reported to range from 3 to 27 days. Following successive weekly doses, the half-life increases and may be 14 to 40 days after the third dose and up to 168 days after the eleventh weekly dose.

Protein Binding
In plasma, 95-99% of the drug is bound to albumin fraction.

[1]. Glutathione and glutaredoxin act as a backup of human thioredoxin reductase 1 to reduce thioredoxin 1 preventing cell death by aurothioglucose. J Biol Chem. 2012 Nov 2;287(45):38210-9.

[2]. Anti-rheumatic compound aurothioglucose inhibits tumor necrosis factor-alpha-induced HIV-1 replication in latently infected OM10.1 and Ach2 cells. Int Immunol. 1999 Feb;11(2):143-50.

[3]. The thioredoxin reductase-1 inhibitor aurothioglucose attenuates lung injury and improves survival in a murine model of acute respiratory distress syndrome. Antioxid Redox Signal. 2014 Jun 10;20(17):2681-91.

[4]. Hypolipidemic effect of pantothenic acid derivatives in mice with hypothalamic obesity induced by aurothioglucose. Exp Toxicol Pathol. 2001 Oct;53(5):393-8.

Aurothioglucose, also known as gold thioglucose, was formerly used to treat rheumatoid arthritis. Contemporary research on the effect of gold salts treatment began in 1935, primarily to reduce inflammation and to slow disease progression in patients with rheumatoid arthritis. The use of gold compounds has decreased since the 1980s owing to numerous side effects, limited efficacy, and slow onset of action. Many if not most gold compounds that were indicated for rheumatoid arthritis therapy have since been replaced with the use of various current disease modifying anti-rheumatic drugs (DMARDs) like methotrexate and others, which are far more effective.
A thioglucose derivative used as an antirheumatic and experimentally to produce obesity in animals.
See also: Aurothioglucose (annotation moved to).

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Drug Indication
Aurothioglucose is indicated for the adjunctive treatment of early active adult and juvenile type rheumatoid arthritis that is not adequately controlled by other anti-inflammatory agents and conservative measures like salicylate, glucocorticoids, etc.. In chronic, advanced cases of rheumatoid arthritis, such gold therapy is not demonstrated to be as valuable. Antirheumatic measures such as salicylate and other anti-inflammatory drugs (both steroidal and non steroidal) may be continued after initiation of gold therapy. After improvement commences, these measures may be discontinued slowly as symptoms permit.

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Mechanism of Action
Rheumatoid arthritis is an autoimmune disease in which the body's immune system mistakenly attacks the lining of various skeletal bone joints of the body. These attacks are facilitated by various pro-inflammatory immune cells and agents like cytokines, histamines, mast cells, macrophages, monocytes, lymphocytes, leukocytes, and many others. The longterm result of this unwanted immune response is chronic inflammation and painful tissue damage. The cause of the malfunctioning immune system in rheumatoid arthritis is unknown and there is no definitive cure for the condition. Similarly, the mechanism of action of aurothioglucose is also not well elucidated. Nevertheless, some studies have suggested that the combination of both the sulfhydryl ligand and aureus cation present in aurothioglucose elicits an inhibitory effect on adenylyl cyclase activity in human lymphocyte membranes and in membranes of T and B lymphocyte subsets. In particular, such inhibition of the activity of adenylyl cyclase and its various isoforms would theoretically also limit the cyclases' ability to induce mast cell degranulation and histamine release, to enhance respiratory burst effects, to stimulate the action of resting macrophages, to induce and activate phagocytes, to induce neutrophil chemotaxis, etc. - all of which are pro-inflammatory actions.
The effects of aurothioglucose, on basal and forskolin-activated adenylyl cyclase activity in human total lymphocyte membranes and in membranes of T and B lymphocyte subsets /was studied/. The gold compounds inhibited adenylyl cyclase activity. This inhibitory effect required the presence of both the sulfhydryl ligands and aurous cation. Regulation of lymphocyte adenylyl cyclase by gold compounds represents a potential mode of action of these drugs in rheumatic disease.
Transcription factor NF-kappaB controls the expression of a number of genes including those for cell adhesion molecules such as E-selectin, ICAM- 1 and VCAM- 1. These cell adhesion molecules are known to play important roles in a critical step of tumor metastasis; the arrest of tumor cells on the venous or capillary bed of the target organ. NF-kappaB is activated by extracellular signals such as those elicited by the proinflammatory cytokines, TNF and IL-1. The adhesion of tumor cells to IL-1 beta-treated HUVEC /human umbilical vein endothelial cells/ was inhibited by gold compounds such as aurothioglucose.

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Therapeutic Uses
... Aurothioglucose ... /is/ indicated in the treatment of adult or juvenile rheumatoid arthritis. ... /This agent is/ usually used for treating patients who show evidence of continued or additional disease activity despite conservative therapy, e.g., with salicylates (especially aspirin) or other nonsteroidal anti-inflammatory agents, glucocorticoids, etc. /Included in US product labeling/
Gold compounds are used in the treatment of these rheumatic conditions / psoriatic arthritis, Felty's syndrome/. /Gold compounds; NOT included in US product labeling/

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Drug Warnings
Patients intolerant of parabens may be intolerant of parenteral aurothioglucose, which may contain propylparaben.
Patients sensitive to sesame products may also be sensitive to the sesame oil vehicle of parenteral aurothioglucose.
Dermatitis is the most common reaction. Pruritus should be considered a warning signal of an impending cutaneous reaction. Erythema and occasionally the more severe reactions such as popular, vesicular, and exfoliative dermatitis leading to alopecia and shedding of the nails may occur. Chrysiasis (gray-to-blue pigmentation) has been reported, especially in photo-exposed areas. Gold dermatitis may be aggravated by exposure to sunlight, or an actinic rash may develop.
Stomatitis is the second most common adverse reaction. Shallow ulcers on the buccal membranes, on the borders of the tongue and on the palate, diffuse glossitis , or gingivitis may be preceded by the sensation of metallic taste. Careful oral hygiene is recommended. Inflammation of the upper respiratory tract, pharyngitis, gastritis, colitis, tracheitis, and vaginitis have also been reported. Conjunctivitis is rare.
For more Drug Warnings (Complete) data for AUROTHIOGLUCOSE (11 total), please visit the HSDB record page.

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Pharmacodynamics
After administration, patient serum levels of gold rise sharply but decline over the following week. Peak levels with aqueous preparations are higher and decline faster than those with oily preparations. Regular weekly administration produces a continuous rise in the basal value for several months, after which the serum level becomes relatively stable. After a standard weekly dose, considerable individual variation in the levels of gold can be observed. A steady decline in gold levels occurs when the interval between injections is lengthened, and small amounts may be found in the serum for months after discontinuation of therapy. The incidence of toxic reactions is seemingly unrelated to the plasma level of gold, but may perhaps be more associated with the total cumulative content of gold in the body.

C6H11AUO5S.XH2O

392.1756

391.999

12192-57-3

12192-57-3 (anhydrous);

454937

White to yellow solid powder

4

6

1

13

160

4

C([C@@H]1[C@H]([C@@H]([C@H](C(O1)[S-])O)O)O)O.[Au+]

XHVAWZZCDCWGBK-BMZZJELJSA-M

InChI=1S/C6H12O5S.Au/c7-1-2-3(8)4(9)5(10)6(12)11-2;/h2-10,12H,1H2;/q;+1/p-1/t2-,3-,4+,5-,6?;/m1./s1

gold(1+);(3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxane-2-thiolate

Aurothioglucose SKF 10056 Solganal

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~125 mg/mL (~318.73 mM)
DMSO : ~6 mg/mL (~15.30 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)