Although auranofin is a medication that has been approved to treat rheumatoid arthritis, it is also being researched for possible therapeutic uses in cancer and maybe neurodegeneration. Cells are induced by auranofin via the Bax/Bak induction pathway. In SKOV3 cells, auranofin inhibits the cell division and rapid death in a dose- and time-dependent manner. Treatment with auranofin can decrease the expression of anti-solvent Bcl-2 in SKOV3 cells, raise the protein levels of apoptosis-inducing proteins Bax and Bim, and stimulate ischemia caspase-3 [2]. The lipophilic gold compound auranofin has immunosuppressive and anti-inflammatory properties. Following auranofin treatment, auranofin stain PC3 human significantly regulates cell growth activity, with an IC50 value of 2.5 μM after 24 hours [3].

Reduced paw edema markers, full restoration of suppressed IL-2 production, and decreased elevation of IL-1 production were the outcomes of auranofin-treated zodiac arthritic markers as a preventive measure[4]. However, there was no response to suppressed IL-3 production.

Absorption, Distribution and Excretion
Following a single dose of auronorgestrel, approximately 60% of the absorbed gold (15% of the administered dose) is excreted in the urine; the remainder is excreted in the feces. In the body, approximately 60% of the gold in auronorgestrel is bound to serum proteins. Of the gold bound to serum proteins, 82% is bound to albumin, and the remainder is bound to α1-, α2-, and β-globulins, and may also be bound to IgG. The free gold content in serum from auronorgestrel is less than 1-2%; the serum free gold concentration achieved by auronorgestrel appears to be similar to that achieved by sodium auronorgestrel thiomalate. After multiple oral administrations of auronorgestrel in animals, the gold is primarily distributed in the kidneys, where the highest concentration is observed; gold is also distributed to the spleen, lungs, adrenal glands, and liver, and lower concentrations are distributed to the heart, testes, gastrointestinal tract, muscles, eyes, fat, and brain. In animals (possibly including humans), a small amount of gold from auronorgestrel is distributed into the bile. Synovial gold concentrations in rheumatoid arthritis patients treated with auronoxine were significantly lower than those treated with injectable gold preparations, but the ratio of blood to synovial gold concentrations during auronoxine treatment was similar to that during injectable gold preparation treatment (approximately 1.7:1). Preliminary data showed that, unlike the gold accumulation in the skin during injectable gold preparation treatment, there was almost no gold accumulation in the skin during auronoxine treatment. During auronoxine treatment, there was almost no gold accumulation in the hair or nails, and to date, even at cumulative doses as high as 6.1 g, no gold accumulation has been detected in the cornea or lens.
In healthy adults, the average peak serum gold concentration 2 hours after a single oral dose of 6 mg auronoxine is 0.025 μg/mL (range: 0.014–0.046 μg/mL). Steady-state serum gold concentrations are typically reached after 8–12 weeks following multiple oral doses of this drug in rheumatoid arthritis patients, but in some patients it may take 13–16 weeks. Despite significant inter-individual variability, once steady-state serum gold concentrations are reached during olaranofen treatment, intra-individual differences in serum gold concentrations appear to be small with continued administration. Animal studies suggest that the ligands of olaranofen are almost completely absorbed; since only a very small amount of gold is absorbed, it is assumed that the drug undergoes extensive disruption of coordination bonds in the gastrointestinal tract. Some experimental data indicate that olaranofen can loosely and reversibly adsorb onto the gastrointestinal mucosa. Other experimental data suggest that gold-containing olaranofen may be absorbed via the mucosa, and its initial metabolic process may involve deacetylation within the gastrointestinal mucosa. For more complete data on the absorption, distribution, and excretion of olaranofen (9 types), please visit the HSDB records page. Metabolism/Metabolites: Metabolism is extremely rapid, with intact molecules not detected in the blood. In patients taking sodium gold thiomalate, the predominant gold species in urine is [Au(CN)2]-, and low molecular weight infiltrates are also visible in the blood. The same compound was also detected in the urine and blood of patients taking aurinofen. Aurinofen, 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranose-S-(triethylphosphine)-gold(I), ... is metabolized upon contact with the intestinal wall of hamsters or rats to produce the deacetylated form of the drug. This product, 1-thio-β-D-glucopyranose-S-(triethylphosphine)-gold(I), crosses the intestinal wall of hamsters or rats in an intestinal inversion experiment... Efflux of gold in erythrocytes (RBCs) exposed to 10–100 μM aurinofen and triethylphosphine (2,3,4,6-tetra-O-acetyl-1-β-D-glucopyranose-S-)gold(I) was investigated. Gold was allowed to accumulate in RBCs in whole blood, which were then placed in fresh plasma or buffered saline solution. …[14C] Glutathione was generated via in situ labeling and subsequently effluxed, binding to albumin and gold. This was the first direct evidence that the albumin-gold-glutathione complex (AlbSAuSG) may be a circulating metabolite of aurnofen, formed after the replacement of both of aurnofen's original ligands.

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Biological Half-Life
The mean terminal plasma half-life of aurnofen gold at steady state is 26 days (range 21 to 31 days; n = 5). The mean terminal in vivo half-life is 80 days (range 42 to 128 days; n = 5). In patients with rheumatoid arthritis receiving 6 mg auranofen daily, the mean terminal plasma half-life and biological half-life of auranofen after the first dose were 17 days (range: 11–23 days) and 58 days (range: 30–78 days), respectively; after 6 months of treatment at the same dose, the mean terminal plasma half-life and biological half-life of auranofen were 26 days (range: 21–31 days) and 81 days (range: 42–128 days), respectively.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
It has not been studied whether gold is excreted into breast milk after taking aurinofen. Case reports of other gold salts show that small amounts of gold are present in breast milk, and at least a small amount is absorbed, as it can be detected in infant urine. There are currently no conclusive reports of toxicity. Authors of review articles have differing opinions, with some advising against use and others recommending permissible use. Monitoring breastfed infants for potential adverse reactions appears to be a prudent approach.
◉ Effects on Breastfed Infants
Four infants have been reported to have been breastfed while their mothers were receiving gold therapy (including sodium aurinothiomalate and glucosinolate). One 18-month-old infant developed transient facial edema three months after the mother stopped treatment. This reaction may have been due to the infant ingesting gold from breast milk.
◉ Effects on Lactation and Breast Milk
No relevant published information was found as of the revision date.

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Interactions
...Patients with a history of toxic reactions may be more likely to experience toxicity after taking penicillamine. The time interval between discontinuing gold preparations and starting penicillamine does not affect the incidence of toxicity. Skin rash during gold preparation treatment does not appear to affect the occurrence of skin rash during penicillamine treatment, but patients who have proteinuria or bone marrow suppression during gold preparation treatment may have an increased risk of similar side effects after taking penicillamine.
In a single case report, there was evidence that concomitant administration of lidaura (olanofen) and phenytoin sodium may lead to elevated phenytoin sodium blood concentrations.

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Non-human toxicity values
Oral LD50 in rats: 265 mg/kg
Oral LD50 in mice: 310 mg/kg

[1]. The thioredoxin reductase inhibitor auranofin triggers apoptosis through a Bax/Bak-dependent process that involves peroxiredoxin 3 oxidation. Biochem Pharmacol. 2008 Oct 30;76(9):1097-109.

[2]. Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53. Int J Oncol. 2014 Oct;45(4):1691-8.

[3]. Auranofin promotes mitochondrial apoptosis by inducing annexin A5 expression and translocation in human prostate cancer cells. J Toxicol Environ Health A. 2014;77(22-24):1467-76.

[4]. Effect of auranofin treatment on aberrant splenic interleukin production in adjuvant arthritic rats. J Immunol. 1987 Nov 15;139(10):3268-74.

[5]. Metallodrug ranitidine bismuth citrate suppresses SARS-CoV-2 replication and relieves virus-associated pneumonia in Syrian hamsters. Nat Microbiol. 2020 Oct 7.

Therapeutic Uses
Aurinofen is indicated for the treatment of rheumatoid arthritis in adults, and may also be used to treat juvenile arthritis (not included on the US product label). ...Gold compounds may induce remission or suppression of rheumatoid arthritis. In chronic advanced rheumatoid arthritis, they can prevent further damage to affected joints; however, they cannot reverse existing damage. (Included on the US product label) Drug Warnings Aurinofen appears to be less toxic and better tolerated than currently available injectable gold compounds, with a significantly lower rate of patients discontinuing treatment due to adverse reactions (approximately 15-20%); however, more experience is needed to more fully characterize the adverse reactions of aurinofen, especially in the context of long-term treatment. Compared to injectable gold preparations, aurinofen produces more gastrointestinal adverse reactions, including those severe enough to require discontinuation, but its mucocutaneous (and possibly renal) adverse reactions are fewer and significantly less severe than those of injectable gold preparations. The overall difference in discontinuation rates due to toxicity between auronoxine and injectable gold formulations is primarily due to the lower incidence and severity of auronoxine-related mucocutaneous adverse reactions. The incidence and severity of other adverse reactions caused by auronoxine appear to be comparable to those caused by injectable gold formulations. The most common adverse reaction to auronoxine is changes in bowel habits, including increased frequency of bowel movements, loose stools, or diarrhea, occurring in approximately 45-50% of patients. Bowel habit changes caused by auronoxine are most likely to occur within the first 3 months of treatment, appear to be dose-related, and may be accompanied by abdominal cramps; these symptoms typically occur primarily within the first few hours after administration. The mechanism of gastrointestinal toxicity is not fully understood, but may be related to the drug's direct effect on intestinal water and electrolyte absorption. Bowel habit changes caused by olaranoxine are likely self-limiting and resolve spontaneously with continued treatment, or are usually controlled by dose reduction or temporary discontinuation (e.g., 3-7 days). Changes in bowel habits in some patients can be managed by temporarily taking antidiarrheal medication (e.g., diphenoxylate hydrochloride), oral iron supplements (for patients with iron deficiency anemia), or increasing dietary fiber intake. Approximately 4-6% of patients require discontinuation of olaranofin due to severe bowel habit changes. Some patients, especially elderly patients, may find the changes in bowel habits beneficial. About 14% of patients receiving olaranofin experience abdominal cramps or pain, of whom about 1% require discontinuation. About 10% of patients experience nausea (with or without vomiting), of whom about 1% discontinue the medication. About 13% of patients experience other gastrointestinal adverse reactions, of whom about 1% discontinue the medication. Gastrointestinal adverse reactions include anorexia, indigestion, and bloating in 3-9% of patients; constipation and taste disturbances in 1-3% of patients; gastrointestinal bleeding, melena, and positive fecal occult blood tests in less than 1% of patients; and dysphagia and ulcerative colitis in less than 0.1% of patients. There have been reports of eosinophilic enterocolitis. ... Rare reports of upper abdominal pain and erosive gastritis in patients taking olaprofen. Skin and mucosal adverse reactions are the second most common adverse reactions to olaprofen. Approximately 24% of patients receiving this drug develop a rash, of which about 3% discontinue the drug; approximately 17% of patients experience pruritus, of which about 1% discontinue the drug. Pruritus usually precedes the rash and should be considered a warning sign of an impending skin reaction. Although there are currently no reports of such reactions caused by aurinofen, the most serious skin reaction to injectable gold preparations has been reported as systemic exfoliative dermatitis. Dermatitis caused by gold preparations may be exacerbated by sunlight exposure or develop into actinic rashes. Approximately 1-3% of patients taking aurinofen develop urticaria, approximately 2.5% develop alopecia or alopecia areata, and less than 0.1% develop angioedema. For more complete data on drug warnings for aurinofen (13 in total), please visit the HSDB records page.

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Pharmacodynamics
Aurinofen is a gold salt used to treat inflammatory arthritis. Gold salts are often considered second-line drugs because they are typically considered when arthritis does not respond to anti-inflammatory medications (NSAIDs and corticosteroids).

678.132

34031-32-8

24199313

White to off-white solid powder

425.5ºC at 760mmHg

103 - 105ºC

298ºC

2.792

0

10

12

32

532

0

[Au+].[S-]C1([H])C([H])(C([H])(C([H])(C([H])(C([H])([H])OC(C([H])([H])[H])=O)O1)OC(C([H])([H])[H])=O)OC(C([H])([H])[H])=O)OC(C([H])([H])[H])=O.P(C([H])([H])C([H])([H])[H])(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])[H]

AUJRCFUBUPVWSZ-UHFFFAOYSA-M

InChI=1S/C14H20O9S.C6H15P.Au/c1-6(15)19-5-10-11(20-7(2)16)12(21-8(3)17)13(14(24)23-10)22-9(4)18;1-4-7(5-2)6-3;/h10-14,24H,5H2,1-4H3;4-6H2,1-3H3;/q;;+1/p-1

gold(1+);3,4,5-triacetyloxy-6-(acetyloxymethyl)oxane-2-thiolate;triethylphosphane

SKF-D-39162Auranofin SKF-39162 SKF D 39162 SKFD-39162 SKF 39162NSC 321521, Ridauragold thiolSKFD39162 Ridaura

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO : ~50 mg/mL (~73.48 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.67 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.08 mg/mL (3.06 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with heating and sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (3.06 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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