A Comprehensive Monograph on Auranofin: From Chrysotherapy to a Modern Polypharmacological Agent

Section 1: Executive Summary

Auranofin (brand name Ridaura®) represents a unique and compelling case study in the lifecycle of a pharmaceutical agent. Initially developed and approved in 1985 as the first orally active gold-containing compound, it was introduced as a novel disease-modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis.[1] Its development marked a significant advancement in chrysotherapy, offering a more convenient and generally better-tolerated alternative to the injectable gold salts of its era.[1] However, the subsequent emergence of more potent and effective DMARDs, such as methotrexate and a host of biologic agents, combined with a significant adverse effect profile associated with its long-term use and commercial decisions by its manufacturer, led to a substantial decline in its clinical application for rheumatological conditions.[5]

In recent years, Auranofin has undergone a remarkable renaissance, driven not by its original indication but by a profound and detailed elucidation of its molecular mechanisms of action. The central discovery that Auranofin is a potent and irreversible inhibitor of the selenoenzyme thioredoxin reductase (TrxR) has repositioned it from a niche antirheumatic agent to a powerful polypharmacological tool with a broad spectrum of potential therapeutic applications.[7] Inhibition of the TrxR/thioredoxin system, a critical cellular antioxidant and redox-regulating pathway, provides a unifying mechanistic rationale for Auranofin's potent activity in diverse pathological contexts. By disrupting cellular redox homeostasis and inducing significant oxidative stress, Auranofin selectively triggers cell death in cells that are highly dependent on this system for survival, a characteristic feature of many cancer cells and pathogenic organisms.[6]

This mechanistic understanding has fueled a wave of drug repurposing research, establishing Auranofin as a promising candidate agent in oncology, infectious diseases, and other inflammatory conditions. Extensive preclinical evidence and a growing number of clinical trials are now evaluating its efficacy against various solid tumors and hematologic malignancies, including ovarian cancer and chronic lymphocytic leukemia.[12] Simultaneously, its potent activity against a wide range of pathogens—including parasitic protozoa such as

Entamoeba histolytica and Giardia lamblia, multidrug-resistant bacteria like MRSA, and viruses including HIV and SARS-CoV-2—has opened new frontiers in anti-infective therapy.[15] Notably, its pharmacokinetic profile, characterized by low oral absorption and high fecal concentration, has proven to be a distinct advantage for treating gastrointestinal parasitic infections.[18]

While the drug carries a significant safety profile, including a US Boxed Warning for potential gold toxicity, decades of clinical use have rendered these risks well-characterized and manageable through established monitoring protocols.[20] This known safety profile, particularly in the context of new, short-term therapeutic regimens, provides a solid foundation for its continued clinical investigation. Auranofin's journey from a superseded arthritis drug to a modern investigational agent serves as a paradigm for drug repurposing, demonstrating how a deeper understanding of molecular pharmacology can unlock the latent potential of established medicines and create entirely new therapeutic opportunities.

Section 2: Compound Identification and Physicochemical Profile

A comprehensive understanding of Auranofin begins with its fundamental chemical identity and physical properties. These characteristics not only define the molecule but also dictate its formulation, stability, and pharmacokinetic behavior, distinguishing it from earlier chrysotherapeutic agents and enabling its unique clinical applications.

2.1. Nomenclature and Identifiers

To ensure unambiguous identification across scientific literature, regulatory databases, and clinical practice, Auranofin is cataloged under a variety of names and standardized identifiers.

• Chemical Name (IUPAC): The formal chemical name is gold(+1) cation; (2S,3R,4S,5R,6R)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxane-2-thiolate; triethylphosphane.[2]
• Common Name: Auranofin.[1]
• Brand Names: It is most widely known by its commercial brand name, Ridaura®.[2]
• Synonyms and Code Names: During its development and in various research contexts, it has been referred to by the codes SK&F-39162 and SK-39162, as well as NSC 321521 and MMV688978.[2]
• Key Identifiers: Standardized identifiers facilitate its tracking in global databases:
• CAS Number: 34031-32-8.[8]
• DrugBank ID: DB00995.
• FDA UNII: 3H04W2810V.[4]
• ATC Code: M01CB03, which classifies it under the "Gold preparations" category of specific antirheumatic agents.[4]

2.2. Chemical Structure and Formula

Auranofin is a complex organogold compound, a structural class that confers its unique biological activities.

• Molecular Formula: The empirical formula is .[8]
• Molecular Weight: The molecular weight is consistently reported as 678.48 to 678.5 g/mol.[8]
• Structural Definition: Auranofin is defined as an S-glycosyl compound. Its structure consists of a central gold(I) atom coordinated to two distinct ligands: a sulfur atom from a 2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranose moiety and a phosphorus atom from a triethylphosphine moiety.[4] The gold exists in the Au(I) oxidation state, which is stabilized by these "soft" ligands (thiolate and phosphine) and is the primary oxidation state that remains stable in biological systems.[25] This monomeric, linear gold(I) complex contains approximately 29% gold by weight.[25]

2.3. Physicochemical Properties

The physical properties of Auranofin are critical to its formulation as an oral drug and its behavior in biological systems. Its lipophilic character is a key design feature that was intentionally engineered to allow for gastrointestinal absorption, a stark contrast to the hydrophilic, polymeric nature of older injectable gold salts like sodium aurothiomalate.[26] This fundamental difference in chemical architecture is directly responsible for Auranofin's status as the first orally active chrysotherapeutic agent, and it profoundly influences its entire pharmacokinetic and clinical profile.[1]

• Physical Appearance: It is a white to off-white, odorless, crystalline solid or powder.[4]
• Solubility: Auranofin is practically insoluble in water but is soluble in organic solvents such as dimethyl sulfoxide (DMSO) and 100% ethanol.[4]
• Melting Point: The melting point is reported in the range of 110–115 °C.[4]
• Stability and Storage: The compound is unstable when exposed to light and heat.[7] The powder may darken slightly upon exposure to strong light or temperatures of 60 °C or higher, which signifies a degree of chemical degradation.[7] Consequently, it must be stored protected from light in tight, light-resistant containers at controlled room temperature (15–30 °C).[20] When stored at -20 °C, it is reported to be stable for at least two years.[8]

Table 1: Chemical and Physical Properties of Auranofin

Property	Value	Source Snippet(s)
IUPAC Name	gold(+1) cation; (2S,3R,4S,5R,6R)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxane-2-thiolate; triethylphosphane	2
Common Name	Auranofin	1
Brand Name	Ridaura®	2
CAS Number	34031-32-8	8
Molecular Formula		8
Molecular Weight	678.48 g/mol	23
Physical Appearance	White to off-white, odorless, crystalline solid	7
Solubility	Insoluble in water; Soluble in DMSO and ethanol	7
Melting Point	110–115 °C	4
Stability	Unstable to light and heat; requires protection from light	7

2.4. Manufacturing Process

The synthesis of this complex organometallic drug is a multi-step process detailed in the originating patents and literature. The manufacturing process can be summarized in two principal stages [4]:

1. Synthesis of the Gold Intermediate: The process begins with the preparation of triethylphosphine gold chloride. This is achieved by reacting gold acid chloride trihydrate with thiodiglycol, followed by the addition of triethylphosphine. This reaction yields the white, needle-like crystals of the triethylphosphine gold chloride intermediate.[4]
2. Formation of Auranofin: The final product is formed by reacting the triethylphosphine gold chloride intermediate with S-(2,3,4,6-tetra-O-acetylglucopyranosyl)-thiopseudourea hydrobromide in the presence of potassium carbonate. This reaction couples the gold-phosphine complex with the thioglucose moiety, resulting in the precipitation of Auranofin as colorless crystals.[4]

Section 3: Molecular Pharmacology and Pluripotent Mechanisms of Action

The biological activity of Auranofin is remarkably diverse, stemming from its ability to interact with multiple cellular targets and disrupt several fundamental biological pathways. The scientific understanding of its mechanism has evolved significantly over time. Initial hypotheses in the 1980s pointed towards vague immunological effects and the alteration of lysosomal enzyme activity.[1] While these effects are observed, subsequent decades of research have refined this picture, revealing a precise molecular mechanism centered on the inhibition of the thioredoxin system. This primary action provides a unifying explanation for its broad therapeutic potential and represents a classic example of scientific progress, where a general clinical observation was ultimately traced to a specific, targetable molecular interaction that now drives modern drug repurposing efforts.

3.1. Primary Mechanism: Inhibition of the Thioredoxin System

The principal and most well-characterized mechanism of action of Auranofin is the potent and irreversible inhibition of the selenoenzyme thioredoxin reductase (TrxR).[6] The TrxR/thioredoxin (Trx) system is a major antioxidant pathway in mammalian cells, essential for maintaining cellular redox homeostasis, regulating signaling pathways, and supporting cell proliferation.

• Molecular Interaction: The gold(I) center of Auranofin exhibits an exceptionally high affinity for sulfhydryl and, particularly, selenol groups.[6] This property directs it to the catalytic site of eukaryotic TrxR, which uniquely contains a highly reactive selenocysteine (Sec) residue.[7] Auranofin forms a stable, irreversible adduct with this Sec residue, effectively inactivating the enzyme.[6] The half-maximal inhibitory concentration ( ) for irreversible inhibition of human TrxR1 is approximately 20 nM, highlighting its remarkable potency.[10]
• Downstream Consequences of TrxR Inhibition: The inactivation of TrxR sets off a cascade of deleterious downstream events, particularly in cells under high intrinsic oxidative stress, such as cancer cells and various pathogens.

1. Disruption of Redox Homeostasis: The primary function of TrxR is to reduce its substrate, thioredoxin (Trx). By inhibiting TrxR, Auranofin prevents this reduction, causing oxidized Trx to accumulate and crippling one of the cell's most important antioxidant defense systems.[10]
2. Induction of Severe Oxidative Stress: The compromised TrxR/Trx system is unable to neutralize reactive oxygen species (ROS) effectively. This leads to a rapid accumulation of ROS, including hydrogen peroxide and superoxide radicals, resulting in a state of severe intracellular oxidative stress.[6] This pro-oxidant effect is central to Auranofin's anticancer and antimicrobial activities.
3. Mitochondrial Dysfunction: Auranofin directly impacts mitochondrial function. It induces the mitochondrial membrane permeability transition, a critical event that leads to the loss of mitochondrial membrane potential, swelling of the mitochondria, and the release of pro-apoptotic factors like cytochrome C into the cytosol.[8]
4. Induction of Programmed Cell Death: The combination of overwhelming oxidative stress, depletion of cellular antioxidants like glutathione, and mitochondrial damage culminates in the activation of the intrinsic apoptotic pathway, leading to programmed cell death.[6] At higher concentrations or in certain cell types, this can also lead to necrotic cell death.[8]

3.2. Modulation of Inflammatory and Signaling Pathways

Beyond its effects on redox balance, Auranofin is a classic polypharmacological agent, concurrently modulating several key signaling pathways involved in inflammation, cell survival, and proliferation. This multifaceted activity likely contributes to its efficacy and explains its broad spectrum of biological effects.

• Inhibition of the NF-κB Pathway: Auranofin is a potent inhibitor of the canonical NF-κB signaling pathway. It achieves this by directly modifying a critical cysteine residue (Cys-179) on the IKKβ subunit of the IκB kinase (IKK) complex.[4] This modification prevents the phosphorylation and subsequent degradation of IκBα, the natural inhibitor of NF-κB. As a result, the pro-inflammatory transcription factor NF-κB remains sequestered in the cytoplasm and cannot translocate to the nucleus to activate the expression of its target genes, which include numerous cytokines, chemokines, and anti-apoptotic proteins.[8]
• Suppression of the JAK/STAT Pathway: Auranofin has been shown to strongly inhibit the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, specifically targeting the JAK1/STAT3 axis.[7] The STAT3 pathway is a critical regulator of cell proliferation, survival, and inflammation and is frequently hyperactivated in various cancers and autoimmune diseases. By down-regulating this pathway, Auranofin suppresses the expression of key immune and survival factors.[7]
• Repression of the NLRP3 Inflammasome: Research indicates that Auranofin can suppress the activation of the NLRP3 inflammasome, a multiprotein complex that plays a central role in innate immunity by processing and activating the pro-inflammatory cytokines IL-1β and IL-18.[8] This action further contributes to its broad anti-inflammatory properties.

3.3. Other Pertinent Biochemical Actions

Auranofin's repertoire of molecular interactions extends to other important cellular systems, further broadening its pharmacological profile.

• Inhibition of Proteasomal Deubiquitinases (DUBs): Auranofin functions as an inhibitor of deubiquitinating enzymes associated with the 19S proteasome.[6] The ubiquitin-proteasome system (UPS) is responsible for the targeted degradation of most cellular proteins and is vital for maintaining cellular homeostasis, regulating the cell cycle, and degrading misfolded or damaged proteins. Cancer cells, due to their high metabolic rate and protein turnover, are particularly dependent on the UPS for survival. By inhibiting DUBs, Auranofin disrupts protein degradation, leading to an accumulation of ubiquitinated proteins, induction of the unfolded protein response, and ultimately apoptosis.[6]
• Inhibition of 5-Lipoxygenase: Auranofin inhibits the enzyme 5-lipoxygenase in human neutrophils.[4] This enzyme is responsible for the first step in the biosynthesis of leukotrienes, which are potent lipid mediators of inflammation. This action likely contributes to its anti-inflammatory effects observed in arthritis.
• Alteration of Lysosomal Enzyme Activity: One of the earliest proposed mechanisms for Auranofin's antirheumatic effect was its ability to modulate lysosomal function in phagocytic cells like macrophages.[1] It has been shown to inhibit the release of lysosomal enzymes, such as β-glucuronidase and lysozyme, from stimulated cells, thereby reducing tissue damage in inflamed joints.[25]

Section 4: Comprehensive Pharmacokinetic and Metabolic Profile

The clinical utility and safety of Auranofin are profoundly shaped by its pharmacokinetic profile. Its journey through the body—encompassing absorption, distribution, metabolism, and excretion (ADME)—is characterized by several unique features, most notably its low oral bioavailability and extremely long elimination half-life. These properties have critical implications for its dosing, onset of action, and the management of its toxicity.

4.1. Absorption, Distribution, Metabolism, and Excretion (ADME)

• Absorption: Following oral administration, Auranofin exhibits low and variable absorption. Only about 20% to 30% of the gold contained in an oral dose is absorbed from the gastrointestinal tract.[20] The absorption process is relatively rapid, with peak plasma concentrations of gold (approximately 6–9 µg/100 mL) typically reached within 1 to 2 hours after dosing.[6]
• Distribution: Once absorbed, gold from Auranofin is extensively bound to plasma proteins, with approximately 60% being protein-bound, primarily to albumin.[6] It also demonstrates a strong affinity for circulating cellular elements, such as red blood cells.[26] The drug distributes into body tissues, and in patients with rheumatoid arthritis, synovial fluid concentrations of gold reach about 50% of the levels found in the blood.[22] Animal studies comparing Auranofin to injectable gold suggest that oral gold has a comparatively lower affinity for tissues of the reticuloendothelial system, such as the liver, kidney, and spleen.[26]
• Metabolism: The metabolic fate of Auranofin is complex and has not been fully elucidated. It is understood that the parent compound is rapidly metabolized, as intact Auranofin is not detectable in the blood.[20] Upon crossing cell membranes, the molecule undergoes dissociation, and the acetyl groups are cleaved from the thioglucose moiety.[25] It is believed that the drug is not broken down into elemental gold.[22] Recent studies using liver microsomes have confirmed that Auranofin is susceptible to hepatic metabolism and have identified aurocyanide as a potential active metabolite. Aurocyanide is metabolically stable, detectable in plasma, and exhibits anti-fibrotic effects, suggesting it may contribute to the overall therapeutic activity of Auranofin.[33] There is no substantive evidence to suggest that the cytochrome P450 (CYP) enzyme system plays a major role in its metabolism.[34]
• Excretion: The elimination of gold following Auranofin administration is predominantly via the feces, which is a direct consequence of its poor oral absorption. Approximately 85% of an administered dose is eliminated in the feces.[6] Of the 20-30% of the drug that is absorbed systemically, about 60% is excreted by the kidneys into the urine, with the remaining 40% being eliminated through biliary excretion into the feces.[22] This dual excretion pathway for the absorbed fraction differs from injectable gold, which is primarily cleared by the kidneys.[26]
• Half-Life and Time to Steady State: Auranofin is characterized by an exceptionally long elimination half-life. Various sources report a plasma half-life in the range of 15 to 31 days, with a commonly cited value of approximately 26 days.[6] A more recent Phase I study in healthy volunteers calculated a terminal half-life of approximately 35 days.[18] This slow elimination means that total body clearance of the drug can take 55 to 80 days.[6] A direct clinical consequence of this long half-life is the prolonged time required to reach steady-state plasma concentrations, which is estimated to be about three months with continuous daily dosing.[40] This pharmacokinetic property is the primary reason for the delayed onset of therapeutic effect in rheumatoid arthritis, where clinical benefits may not become apparent for 3 to 6 months.[1] Furthermore, this "pharmacokinetic memory" means that adverse effects can persist or even first appear long after the drug has been discontinued, necessitating extended monitoring and a recommendation that women of childbearing potential avoid pregnancy for at least six months after their final dose.[42]

Table 2: Summary of Pharmacokinetic Parameters (ADME)

Parameter	Value	Key Clinical Implications	Source Snippet(s)
Oral Bioavailability	~20–30% of gold in dose is absorbed	Low systemic exposure from oral dose; high concentration of unabsorbed drug in GI tract.	22
Time to Peak ()	~1–2 hours	Rapid absorption of the available fraction.	6
Protein Binding	~60% (primarily albumin)	High degree of binding influences distribution and availability of free drug.	6
Primary Excretion Route	~85% of administered dose in feces (unabsorbed); ~60% of absorbed dose in urine.	Dual elimination pathway for absorbed drug; high fecal concentration is advantageous for GI infections.	6
Elimination Half-Life	~26–35 days	Extremely slow elimination; drug accumulation with daily dosing; persistence of effects and toxicity after discontinuation.	18
Time to Steady State	~3 months	Explains the delayed therapeutic onset of action (3-6 months) in chronic conditions like rheumatoid arthritis.	1

4.2. Pharmacokinetic Considerations in Special Populations

The lack of definitive data on Auranofin's pharmacokinetics in patients with organ impairment represents a significant knowledge gap, particularly as the drug is being repurposed for new, often critically ill, patient populations. The available guidance is limited and largely based on clinical caution rather than robust pharmacokinetic studies.

• Renal Impairment: The official manufacturer's labeling provides no specific dosage adjustment recommendations for patients with renal impairment.[20] This is a critical omission, as a substantial portion of the absorbed gold is excreted via the kidneys, and gold itself can be nephrotoxic.[20] In the absence of formal guidance, some clinicians have adopted empirical dose adjustments based on creatinine clearance (CrCl) or glomerular filtration rate (GFR). However, these recommendations vary between sources, creating uncertainty for prescribers. This ambiguity is a major challenge for the safe use of Auranofin in patients with compromised renal function, a common comorbidity in cancer and other serious illnesses for which the drug is being investigated.
• Hepatic Impairment: Similar to renal impairment, the manufacturer's labeling does not provide specific dosage adjustment guidelines for patients with hepatic impairment.[20] The drug is contraindicated in patients with severe hepatological disorders and should be used with caution in those with pre-existing hepatic disease.[42] While evidence suggests Auranofin undergoes hepatic metabolism [33], and rare cases of hepatotoxicity have been reported [42], the precise impact of liver dysfunction on its clearance and exposure is unknown. Interestingly, some preclinical research suggests a potential therapeutic role for Auranofin in mitigating liver fibrosis and nonalcoholic fatty liver disease, adding another layer of complexity to its relationship with liver function.[45]

Table 3: Dosing Adjustments in Renal Impairment

Level of Renal Impairment (CrCl/GFR)	Recommended Dose Adjustment	Source/Caveat	Source Snippet(s)
CrCl 50–80 mL/minute	Reduce dose to 50%	Clinician guidelines (Aronoff, 2007); not in manufacturer's label.	20
GFR 20–50 mL/minute	3–6 mg daily (standard dose)	Pediatric Oncall guidelines; conflicts with other sources.	47
CrCl <50 mL/minute	Avoid use	Clinician guidelines (Aronoff, 2007); not in manufacturer's label.	20
GFR 10–20 mL/minute	3 mg daily	Pediatric Oncall guidelines.	47
GFR <10 mL/minute / Dialysis	Avoid use	Pediatric Oncall guidelines.	47

Section 5: Clinical Application as a Disease-Modifying Antirheumatic Drug (DMARD)

Auranofin was originally developed and approved for the management of rheumatoid arthritis (RA), where it was classified as a disease-modifying antirheumatic drug (DMARD). Its history in this indication provides essential context for its safety profile, dosing, and the factors that ultimately led to its decline in use, paving the way for its modern repurposing.

5.1. Indication and Place in Therapy

• Approved Indication: Auranofin is indicated for the adjunctive treatment of active classical or definite rheumatoid arthritis in adult patients who have shown an insufficient therapeutic response to, or are intolerant of, an adequate trial of one or more non-steroidal anti-inflammatory drugs (NSAIDs).[21] It was considered a second-line agent, intended to be added to a comprehensive baseline therapeutic program rather than used as a monotherapy for initial treatment.[6]
• Off-Label Uses: Based on its immunomodulatory and anti-inflammatory properties, Auranofin has also been used off-label for other inflammatory arthritides, including psoriatic arthritis, as well as for active systemic lupus erythematosus and Felty's syndrome.[22]

5.2. Dosing, Administration, and Clinical Monitoring

• Adult Dosage: The standard initial adult dosage of Auranofin is 6 mg per day. This can be administered either as a single 6 mg dose or divided into 3 mg taken twice daily.[22] Initiating therapy at doses higher than 6 mg daily is not recommended due to an increased incidence of gastrointestinal side effects, particularly diarrhea.[40]
• Dose Titration: The therapeutic response to Auranofin is delayed due to its long half-life. If the clinical response is deemed inadequate after a trial of four to six months at the 6 mg/day dose, the dosage may be increased to a maximum of 9 mg per day, administered as 3 mg three times daily. If the response remains insufficient after an additional three-month trial at the 9 mg/day dose, therapy should be discontinued.[22]
• Clinical Monitoring: The risk of gold-related toxicity necessitates a rigorous monitoring schedule. Before initiating therapy, baseline laboratory tests are required, including a complete blood count (CBC) with differential, platelet count, urinalysis, and renal and liver function tests.[20] During treatment, the CBC, platelet count, and urinalysis (for protein and hematuria) must be monitored at least monthly.[22] Patients should also be regularly examined for skin rashes and stomatitis and questioned about symptoms like pruritus or a metallic taste, which can be early warning signs of toxicity.[20]

5.3. Efficacy and Comparative Status

• Efficacy: As a DMARD, Auranofin was shown to suppress the underlying inflammatory processes of rheumatoid arthritis. Clinical studies demonstrated that it could reduce synovitis, decrease elevated serum levels of immunoglobulins and rheumatoid factors, and in some cases, lead to clinical remission of the disease.[1]
• Limitations: A significant limitation noted in early reviews was that radiological studies were inconclusive regarding Auranofin's ability to halt or slow the progression of erosive bone and cartilage lesions, a key goal of modern RA therapy.[1]
• Comparison to Injectable Gold: When compared to the older standard of injectable gold salts (e.g., sodium aurothiomalate), Auranofin's efficacy was generally considered to be slightly less potent.[1] However, this was often balanced by a more favorable safety profile; while side effects were common with Auranofin, they were generally less severe than those associated with injectable gold, which had a higher incidence of mucocutaneous and renal toxicities.[1]

5.4. Reasons for Decline in Use

The story of Auranofin in rheumatology is a clear example of a drug being superseded as the standard of care evolved. Its decline was not due to a sudden discovery of a new, major safety issue, but rather a gradual shift in the therapeutic landscape that rendered its risk-benefit profile less favorable compared to newer options.

• Emergence of More Effective Therapies: The primary reason for Auranofin's decline was the introduction and widespread adoption of more effective DMARDs. Methotrexate became the anchor drug for RA treatment due to its superior efficacy in controlling disease activity and preventing joint damage. Subsequently, the development of highly effective biologic agents, such as TNF-α inhibitors, revolutionized RA management, setting a new and higher standard for therapeutic outcomes that Auranofin could not match.[6]
• Adverse Effect Profile and Monitoring Burden: While often less severe than injectable gold, the high frequency of adverse effects, especially the 47% incidence of diarrhea, limited its tolerability for long-term, chronic use.[6] The requirement for frequent and diligent laboratory monitoring for potentially severe hematologic and renal toxicities also presented a significant burden for both patients and physicians.[20]
• Commercial Decisions: As its market share dwindled, Auranofin became less profitable for its manufacturer. This led to commercial decisions to cease marketing and withdraw the product from various global markets, further limiting its availability and use.[5]

Section 6: Safety, Tolerability, and Risk Management

The clinical use of Auranofin is intrinsically linked to its well-defined but significant safety profile. Decades of application in rheumatoid arthritis have generated a comprehensive understanding of its potential toxicities, which range from common and manageable side effects to rare but severe and potentially fatal reactions. This knowledge is critical for risk management in its historical indication and provides an essential framework for designing safe clinical trials for its repurposed applications.

6.1. Profile of Adverse Drug Reactions

The potential for gold-induced toxicity is the foremost safety concern with Auranofin, mandating a US Boxed Warning to alert prescribers and patients to the associated risks.

• US Boxed Warning: The prescribing information for Auranofin includes a boxed warning highlighting that the drug contains gold and can cause gold toxicity, which may be severe and, in some cases, fatal. The warning lists key danger signs that require immediate medical attention: a fall in hemoglobin, leukopenia (white blood cell count <4,000/mm³), granulocytopenia (<1,500/mm³), a decrease in platelets (<150,000/mm³), proteinuria, hematuria, pruritus, rash, stomatitis, or persistent diarrhea.[20]
• Most Common Reactions: The adverse effect profile of Auranofin is dominated by gastrointestinal and mucocutaneous reactions.
• Gastrointestinal: Diarrhea or loose stools are the most common adverse effect, reported in approximately 47% of patients. This is often accompanied by abdominal pain (14%), nausea with or without vomiting (10%), anorexia, and flatulence.[1] These symptoms are the most frequent reason for dose reduction or discontinuation and represent the primary difference in the side effect profile compared to injectable gold, which more commonly causes mucocutaneous reactions.[1]
• Dermatological: Skin reactions are very common, with rash occurring in 24% of patients and pruritus (itching) in 17%.[42] These reactions can be exacerbated by exposure to sunlight, potentially leading to an actinic rash.[42] Urticaria and alopecia (hair loss) have also been reported.[42]
• Oral Mucous Membranes: Stomatitis (inflammation and sores in the mouth) is another frequent reaction, affecting about 13% of patients.[42] It can manifest as shallow ulcers on the tongue, palate, or buccal membranes. The development of a metallic taste may precede the onset of stomatitis and should be considered a warning signal.[22]
• Serious and Less Common Reactions: While less frequent, Auranofin can cause severe toxicity affecting multiple organ systems.
• Hematologic: Potentially life-threatening hematologic disorders can occur. These include thrombocytopenia (low platelet count), which may present with purpura or bruising, leukopenia (low white blood cell count), anemia, and eosinophilia.[1] Rare but fatal cases of agranulocytosis and aplastic anemia (bone marrow failure) have been attributed to gold therapy.[22]
• Renal: Gold is a known nephrotoxin. The most common signs of renal toxicity are proteinuria (protein in the urine) and hematuria (blood in the urine).[1] If unrecognized and therapy is continued, these can progress to more severe conditions such as nephrotic syndrome, glomerulonephritis, or acute renal failure.[22]
• Hepatic: Elevations in liver enzymes can occur in 1-3% of patients.[21] Rare cases of cholestatic jaundice and other forms of hepatic dysfunction have been reported.[22]
• Respiratory: Though rare, serious pulmonary complications such as gold bronchitis and interstitial pneumonitis or fibrosis have been associated with gold therapy.[22]

The well-characterized nature of these risks, while significant, provides a clear roadmap for risk mitigation. For its repurposing in acute conditions like parasitic infections, the treatment duration is significantly shorter (e.g., 5-7 days) than the chronic, multi-year therapy used in RA.[54] This drastically reduces the likelihood of developing cumulative toxicities. A Phase I study in healthy volunteers confirmed that a 7-day course of Auranofin was well-tolerated, with only mild, self-resolving adverse events reported.[18] This demonstrates that the safety profile established from chronic use, while cautionary, does not preclude its safe investigation in short-term regimens where the risk-benefit calculation is entirely different.

6.2. Contraindications, Warnings, and Precautions

To ensure patient safety, the use of Auranofin is strictly contraindicated in certain populations and requires careful consideration in others.

• Contraindications: Auranofin is absolutely contraindicated in patients with a known hypersensitivity to the drug or a history of any severe gold-induced toxicity. This includes previous episodes of necrotizing enterocolitis, pulmonary fibrosis, exfoliative dermatitis, bone marrow aplasia, or other severe hematologic disorders.[20] It is also contraindicated in patients with progressive renal disease or severe hepatological disorders.[42]
• Pregnancy and Lactation: Auranofin is classified as Pregnancy Risk Category C. Animal studies have demonstrated that it is both embryotoxic and teratogenic.[42] Therefore, its use is contraindicated in pregnant women. Due to the drug's extremely slow elimination, women of childbearing potential must be advised of the necessity to avoid pregnancy during treatment and for at least six months after discontinuing the drug.[42] It is not known if Auranofin is excreted in human milk, but injectable gold is. Consequently, breastfeeding is not recommended during therapy.[43]
• Precautions: Caution should be exercised when considering Auranofin for patients with pre-existing conditions that could be exacerbated by gold toxicity. This includes patients with inflammatory bowel disease, existing skin rashes, or a history of bone marrow depression.[22]

6.3. Clinically Significant Drug-Drug Interactions

The potential for additive toxicity is a key consideration when Auranofin is used with other medications.

• Phenytoin: Co-administration of Auranofin with the antiepileptic drug phenytoin may lead to increased blood levels of phenytoin, elevating the risk of phenytoin-related toxicity. The mechanism for this interaction is not well understood.[21]
• Myelosuppressive and Nephrotoxic Agents: The concurrent use of Auranofin with other drugs that are known to cause bone marrow suppression or kidney damage is particularly hazardous. Co-administration with penicillamine, which also carries risks of hematologic and renal toxicity, may result in additive toxic effects and should be avoided.[47]
• Immunosuppressants: The concomitant use of Auranofin with other potent immunosuppressive agents—such as azathioprine, methotrexate, or cyclophosphamide—or with high doses of corticosteroids is generally not recommended. This is due to the potential for additive immunosuppression, which could increase the risk of serious infections, and the overlapping potential for organ toxicity.[43]
• Antimalarials: The combination of Auranofin with the antimalarial drug atovaquone/proguanil may increase the risk of toxicity to blood cells and should be avoided.[50]

6.4. Management of Overdosage and Gold Toxicity

There is limited experience with acute Auranofin overdosage. In the event of an acute ingestion, management should include immediate induction of emesis or gastric lavage, along with appropriate supportive care.[22] For the management of severe gold-induced toxic reactions (e.g., severe renal, hematologic, pulmonary, or enterocolitic complications), the primary intervention is the immediate discontinuation of Auranofin. High-dose systemic corticosteroids, such as prednisone at doses of 40 to 100 mg daily in divided doses, are recommended to control the inflammatory component of the reaction. In cases where steroid therapy alone is ineffective, the use of chelating agents, such as dimercaprol (British Anti-Lewisite), may be considered to facilitate the removal of gold from the body.[22]

Section 7: Regulatory History and Global Market Landscape

The regulatory and commercial trajectory of Auranofin is a compelling narrative of a drug's lifecycle, marked by initial success, a decline driven by an evolving therapeutic landscape, and a modern resurgence fueled by scientific innovation in drug repurposing.

7.1. Regulatory Approval History

• Food and Drug Administration (FDA), United States: Auranofin received its initial marketing approval from the US FDA on May 24, 1985, for the treatment of adult rheumatoid arthritis.[2] Decades later, its potential in a new therapeutic area was formally recognized when it was granted an Orphan Drug Designation by the FDA on April 30, 2010, for the "treatment of amebiasis".[60] This designation provides incentives for the development of drugs for rare diseases and signifies regulatory acknowledgment of its promising preclinical data against Entamoeba histolytica. However, it has not yet received formal FDA approval for this orphan indication.
• Therapeutic Goods Administration (TGA), Australia: In Australia, the originally approved tablet formulation of Ridaura (ARTG 13000) is currently listed as being in short supply or unavailable. To address this gap in availability for patients, the TGA has granted a Section 19A approval for the importation and supply of a Canadian-sourced 3 mg capsule formulation of Auranofin. This temporary approval is valid until January 31, 2026, ensuring continued patient access.[49]
• European Medicines Agency (EMA), Europe: Auranofin does not appear to have a centralized marketing authorization that is valid across the entire European Union.[62] Any marketing authorizations in Europe have been granted through national procedures in individual member states.[62] For instance, marketing authorizations have existed in countries like Italy and Sweden. However, many of these national authorizations, particularly in Sweden, appear to have been deregistered over time, reflecting its declining use in rheumatology.[66]

7.2. Market Availability and Commercial Dynamics

• Current Status: Auranofin, under the brand name Ridaura®, remains available by prescription in the United States and Canada.[20] In the US, it is not available as a generic drug, which may impact its cost and accessibility.[20] Its use for its original indication of rheumatoid arthritis has declined dramatically to the point where it is now a rarely used, niche medication in that field.[3]
• Reasons for Market Withdrawal/Decline: The primary driver behind Auranofin's withdrawal from some markets and its overall decline in use was not a new safety concern but rather a commercial decision by the manufacturer.[5] As more effective and convenient treatments for rheumatoid arthritis became the standard of care, Auranofin's market share diminished, making it no longer profitable to produce and market in certain regions. This economic reality, rather than a regulatory mandate, led to its reduced global footprint.[5]

7.3. Market Analysis and Future Projections

Despite its near-obsolescence in rheumatology, the market for Auranofin is experiencing a remarkable revitalization, driven entirely by the promise of drug repurposing. This shift illustrates how a drug's commercial value can be completely redefined by new scientific understanding of its pharmacology.

• Market Growth: Recent market analysis projects significant growth for the Auranofin market. One report forecasts an increase from approximately USD 219 million in 2024 to a projected value of USD 291 million by 2030, reflecting a compound annual growth rate (CAGR) of 4.85%.[68]
• Drivers of Growth: This projected growth is not based on its use in arthritis but is a direct result of its expanding clinical portfolio in new therapeutic areas. The concerted research into its applications in oncology (specifically leukemia and lymphoma) and other autoimmune disorders is creating a new market for the compound.[68]
• Shifting Market Landscape: The renewed interest is reshaping the market's structure. The primary end-users are shifting from outpatient rheumatology clinics to specialized hospital settings, oncology centers, and even home care. Distribution channels are also expanding to include online and specialty pharmacies to support these new treatment paradigms.[68] The market is no longer for an "arthritis drug" but for a "TrxR inhibitor," a fundamental redefinition that has rescued a legacy drug from commercial extinction and created an entirely new and growing market based on its molecular mechanism.

Section 8: The Renaissance of Auranofin: Drug Repurposing and Novel Therapeutic Frontiers

The most exciting chapter in the story of Auranofin is its modern renaissance as a repurposed drug. A deep understanding of its potent inhibitory effect on the thioredoxin reductase system has unlocked a vast landscape of new therapeutic possibilities, positioning it as a promising investigational agent for some of the most challenging diseases, including cancer and a wide array of infectious diseases.

8.1. Applications in Oncology

The rationale for repurposing Auranofin in oncology is exceptionally strong and mechanistically driven. Many types of cancer cells exhibit a heightened state of intrinsic oxidative stress due to their rapid proliferation and metabolic activity. To survive, they often upregulate antioxidant systems, with the TrxR/Trx pathway being a critical component. This creates a therapeutic vulnerability: by inhibiting TrxR, Auranofin can selectively push these already-stressed cancer cells over the edge, leading to catastrophic oxidative damage and cell death, while having a lesser effect on normal cells with a lower baseline level of oxidative stress.[7] This primary mechanism is complemented by its ability to inhibit other key pro-survival pathways frequently dysregulated in cancer, such as NF-κB, STAT3, and the PI3K/AKT/mTOR axis, and to disrupt the ubiquitin-proteasome system.[8]

• Clinical Trials in Solid Tumors:
• Ovarian, Peritoneal, and Fallopian Tube Cancer: This has been an area of significant clinical investigation.
• NCT01747798 (Phase 0/Early Phase 1): This pilot trial evaluated Auranofin monotherapy in patients with recurrent cancer whose only sign of progression was a rising CA-125 tumor marker. The study, completed in 2019, found that the drug was well-tolerated, with only Grade 1 and 2 adverse events reported. In terms of efficacy, 4 of 9 evaluable patients achieved stable disease, and one patient experienced a notable and sustained drop in CA-125 of over 50%. However, the overall benefit was limited, with a median progression-free survival (PFS) of only 2.8 months. The investigators concluded that while safe, Auranofin monotherapy offered only modest clinical benefit in this setting and did not warrant further development as a single agent.[12]
• NCT03456700 (Phase 2): This trial investigated Auranofin in combination with the mTOR inhibitor sirolimus for patients with recurrent serous ovarian cancer. The study was ultimately terminated. Published results indicated that while the combination was generally well-tolerated, the clinical benefits were modest and did not support its adoption as a standard treatment for this patient population.[12]
• Lung Cancer (NSCLC & SCLC): Preclinical studies have demonstrated that Auranofin has potent anti-proliferative and pro-apoptotic effects in various lung cancer cell lines, driven by the induction of oxidative stress and depletion of glutathione.[69] This led to a clinical trial, NCT01737502 (Phase 1/2), which evaluated Auranofin in combination with sirolimus in patients with advanced lung cancer. The trial is listed as completed, but the final results have not yet been made publicly available.[12]

The modest results from monotherapy trials in solid tumors suggest that Auranofin's future in oncology likely lies in rationally designed combination therapies. Its ability to induce a pro-oxidant state can sensitize cancer cells to the effects of other treatments, including conventional chemotherapy, targeted agents, and immunotherapy.[10] The initial trials, while not demonstrating breakthrough efficacy, have provided crucial safety data and have correctly redirected research efforts toward identifying optimal combination partners to exploit this mechanism.

• Clinical Trials in Hematologic Malignancies:
• Chronic Lymphocytic Leukemia (CLL): Preclinical work in CLL has been particularly promising. Auranofin was shown to be highly effective at killing CLL cells in vitro, including those with high-risk genetic features like deletions of chromosome 11q or 17p, and was able to overcome the apoptosis resistance conferred by protective stromal cells in the tumor microenvironment.[14] In an in vivo mouse model of CLL, Auranofin treatment significantly reduced the tumor burden and improved survival.[14] This strong preclinical rationale led to a Phase 2 clinical trial, NCT01419691, for patients with relapsed or refractory CLL, small lymphocytic lymphoma (SLL), or prolymphocytic lymphoma (PLL). The trial was completed in 2016. While the full study results have not been formally published or posted, a preliminary report analyzing blood samples from six patients treated on the trial provided important in-vivo proof of mechanism. The analysis showed that within 24 hours of the first dose, Auranofin induced a significant (1.8-fold) increase in ROS levels and a corresponding increase in apoptosis in the patients' circulating CLL cells.[75]

Table 4: Summary of Major Clinical Trials in Oncology

NCT Identifier	Phase	Indication	Intervention	Status	Key Outcomes/Conclusions	Source Snippet(s)
NCT01747798	Early 1	Recurrent Ovarian, Peritoneal, Fallopian Tube Cancer	Auranofin Monotherapy	Completed	Well-tolerated; 4/9 patients had stable disease. Median PFS of 2.8 months. Modest clinical benefit does not support use as monotherapy.	70
NCT03456700	2	Recurrent Serous Ovarian Cancer	Auranofin + Sirolimus	Terminated	Combination was well-tolerated but showed modest clinical benefits not sufficient to support adoption as a standard treatment.	12
NCT01419691	2	Relapsed/Refractory CLL/SLL/PLL	Auranofin Monotherapy	Completed	Full results not posted. Preliminary data from 6 patients showed increased ROS and apoptosis in CLL cells in vivo after first dose.	14
NCT01737502	1/2	Advanced NSCLC or SCLC	Auranofin + Sirolimus	Completed	Results not yet publicly available.	12

8.2. Applications in Infectious Diseases

Auranofin has emerged as a powerful, broad-spectrum anti-infective agent, with potent activity demonstrated against parasites, bacteria, and viruses. Its most advanced repurposing application is in the treatment of gastrointestinal parasitic infections, where a key pharmacokinetic property—poor oral absorption—has been cleverly leveraged as a therapeutic advantage.

• Antiparasitic Activity: Many protozoan parasites rely heavily on thioredoxin-based redox systems for survival, making them highly susceptible to Auranofin's inhibitory action.[17]
• Entamoeba histolytica (Amebiasis) and Giardia lamblia (Giardiasis): Auranofin has shown remarkable efficacy against these common causes of diarrheal disease. Preclinical studies found it to be approximately 10 times more potent than the standard-of-care drug, metronidazole, against E. histolytica in vitro.[17] Crucially, it is also highly effective against metronidazole-resistant strains of Giardia, addressing a growing clinical challenge.[67]
• Clinical Trials (Amebiasis & Giardiasis): The strong preclinical data led to a structured clinical development program.
• NCT02089048 (Phase 1): This foundational study in healthy volunteers was designed to assess the safety and pharmacokinetics of a short, 7-day course of 6 mg/day Auranofin. The results were pivotal: the regimen was safe and well-tolerated, and it demonstrated that while systemic absorption was low, the concentration of gold in the feces reached 13 µM. This level is more than 25 times the IC50 required to kill E. histolytica and 4 times the IC50 for Giardia. This finding provided powerful proof-of-concept that oral Auranofin could achieve therapeutic concentrations directly at the site of infection in the gut lumen, turning its poor absorption into a significant asset.[18]
• NCT02736968 (Phase 2a): Building on the successful Phase 1 results, this randomized, placebo-controlled trial was initiated to evaluate the clinical efficacy of Auranofin in adult patients with active amebiasis or giardiasis. The study is listed as completed, with results posted in January 2023, though the detailed outcomes are not available in the provided source material.[54]
• Antibacterial Activity: Auranofin disrupts the thiol-redox homeostasis in bacteria, making it a promising antibacterial agent, particularly against Gram-positive pathogens.[8] It has demonstrated potent in vitro activity against clinically important bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and Mycobacterium tuberculosis.[2] Furthermore, its efficacy has been validated in vivo in a murine model of systemic MRSA infection, suggesting its potential for treating severe staphylococcal infections.[8]
• Antiviral Activity: The immunomodulatory and redox-modulating properties of Auranofin have also led to its investigation as an antiviral agent.
• HIV: Auranofin is being explored as a novel strategy to target and reduce the latent HIV viral reservoir that persists in resting T-cells despite effective antiretroviral therapy. By inducing oxidative stress in these cells, it may promote their elimination.[3]
• SARS-CoV-2: Preclinical research conducted during the COVID-19 pandemic suggested that Auranofin could inhibit SARS-CoV-2 replication in human cells at low micromolar concentrations. Its proposed mechanisms include the inhibition of a raft-dependent endocytic pathway used by the virus for cell entry and the attenuation of the hyperinflammatory cytokine response associated with severe COVID-19.[15]

Table 5: Summary of Clinical Trials in Infectious Diseases

NCT Identifier	Phase	Indication	Intervention	Status	Key Outcomes/Conclusions	Source Snippet(s)
NCT02089048	1	Healthy Volunteers (PK for Parasitic Infections)	Auranofin 6 mg/day for 7 days	Completed	Well-tolerated. Established high fecal gold concentrations (13 µM), providing strong rationale for treating GI parasites.	18
NCT02736968	2a	Amebiasis and Giardiasis	Auranofin vs. Placebo	Completed	Efficacy trial. Results posted Jan 2023, but specific outcomes not detailed in available sources.	55

Section 9: Expert Analysis and Future Directions

Auranofin stands at a unique crossroads in pharmaceutical history. Its trajectory encapsulates the evolution of drug development, from empirical use in rheumatology to mechanism-driven repurposing in the modern era. The comprehensive analysis of its properties, clinical history, and recent research reveals a compound of remarkable complexity and renewed promise. This concluding analysis synthesizes the key findings to provide a forward-looking perspective on the challenges and opportunities that will define its future.

9.1. Synthesis: A Tale of Two Drugs

The identity of Auranofin is effectively bifurcated. On one hand, it is a legacy DMARD for rheumatoid arthritis, a relic of the chrysotherapy era. Its use in this chronic setting is defined by modest efficacy compared to modern standards, a slow onset of action, and a significant burden of cumulative toxicity and monitoring. This version of Auranofin has, for sound clinical and commercial reasons, been largely relegated to the past.

On the other hand, a new identity has emerged: Auranofin as a potent, polypharmacological, mechanism-defined agent. This modern Auranofin is best understood not as a "gold salt" but as a "pro-oxidant TrxR inhibitor." This mechanistic re-characterization is the single most important development in its history, providing the unifying scientific rationale for its investigation in oncology, infectious diseases, and other conditions characterized by dysregulated redox signaling. This new identity is associated with short-term, targeted therapeutic regimens where its risk-benefit profile is fundamentally different and potentially far more favorable.

9.2. Challenges in Clinical Translation

Despite the immense promise, the path to translating Auranofin's preclinical potential into new approved indications is fraught with challenges.

• Optimizing the Therapeutic Window: The primary challenge, particularly in oncology, is defining a dose and schedule that maximizes the pro-oxidant, cytotoxic effect on pathological cells while minimizing toxicity to healthy tissues. The drug's extremely long half-life complicates this, as steady-state concentrations are achieved slowly, and drug accumulation can lead to delayed toxicity. This makes chronic dosing regimens for cancer treatment inherently difficult to manage.
• Biomarker Development: To move beyond empirical use, the development of predictive biomarkers is essential. Identifying which patients are most likely to respond would significantly improve the therapeutic index. For instance, tumors with high baseline expression of TrxR1, or those with underlying defects in other antioxidant pathways (making them more reliant on the Trx system), could be prime candidates for Auranofin therapy.[10] Without such biomarkers, clinical trials risk being diluted by non-responders, potentially masking a true effect in a specific subpopulation.
• Commercial and Regulatory Hurdles: As an off-patent drug, Auranofin faces the classic "valley of death" for drug repurposing. The original manufacturer may have little financial incentive to fund the large, expensive Phase 3 trials required to gain approval for a new indication.[5] Future progress will likely depend on a collaborative ecosystem of academic research centers, government funding bodies (such as the NIH, which sponsored the parasitic disease trials), and potentially smaller pharmaceutical companies focused on value-added medicines.

9.3. Future Research and Opportunities

The future of Auranofin lies in leveraging its unique mechanistic properties through intelligent clinical trial design and targeted applications.

• Rational Combination Therapies in Oncology: The most promising path forward in cancer treatment is not as a monotherapy but as a component of a rational combination strategy. Its ability to induce ROS and disrupt redox homeostasis makes it an ideal partner for agents that are either potentiated by oxidative stress or that target parallel survival pathways. Key opportunities include combinations with:
• Conventional Chemotherapies (e.g., platinum agents): To overcome chemoresistance, which is often mediated by enhanced antioxidant capacity.[10]
• Targeted Therapies: Such as PARP inhibitors or AKT inhibitors, where disrupting redox balance can enhance synthetic lethality.[13]
• Immunotherapy: By inducing immunogenic cell death and potentially modulating the tumor microenvironment, Auranofin could synergize with immune checkpoint inhibitors.[13]
• A Broad-Spectrum Anti-Infective: Auranofin's most immediate and tangible opportunity lies in infectious diseases. The full publication of the Phase 2a results for amebiasis and giardiasis (NCT02736968) will be a pivotal event. A positive outcome could lead to a new, much-needed treatment for these widespread parasitic infections, particularly for metronidazole-resistant cases. Beyond this, further clinical investigation is warranted for other pathogens where preclinical data is strong, such as MRSA and tuberculosis.[2]
• Novel Formulation and Delivery: To address the challenges of its long half-life and systemic toxicity, research into novel drug delivery systems could be transformative. The development of formulations that target Auranofin specifically to tumor tissue or sites of infection could dramatically improve its therapeutic index, allowing for higher local concentrations while minimizing systemic exposure.

In conclusion, Auranofin is far more than a historical footnote in the treatment of arthritis. It is a vibrant and clinically relevant molecule whose full potential is only now being realized. Its journey underscores the enduring value of deep pharmacological investigation and its capacity to breathe new life into old drugs, offering new hope for patients with some of the world's most intractable diseases.

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