Auranofin: Uses, Dosage, Side Effects and Interactions

Auranofin, originally developed as an oral gold compound for the treatment of rheumatoid arthritis, has recently gained renewed attention for its diverse biological activities. Beyond its established use in rheumatology, this unique molecule is now being explored as a potential treatment for infections, cancer, and even certain iron disorders. In this comprehensive article, we break down auranofin’s clinical uses, recommended dosages, potential side effects, and known drug interactions, drawing on the latest research and clinical data.

Uses of Auranofin

Auranofin’s therapeutic potential extends well beyond its initial approval as an anti-rheumatic agent. Researchers and clinicians have identified promising activity in a range of diseases, from autoimmune conditions to infectious diseases and certain cancers. This versatility is primarily attributed to its ability to inhibit thioredoxin reductase, an enzyme crucial for maintaining redox balance in cells—a mechanism shared across its various applications.

Indication	Description	Mechanism/Outcome	Sources
Rheumatoid Arthritis	Chronic inflammatory arthritis	Disease-modifying, immune modulation	3 12
Antibacterial	Drug-resistant Gram-positive and TB	Inhibits thioredoxin reductase in bacteria, effective vs. resistant strains	1
Antiparasitic	E. histolytica, Giardia	Broad-spectrum activity, effective in animal and phase I human studies	4
Antifungal	Candida, Cryptococcus	Inhibits fungal mitochondrial protein import, effective in biofilms	5
Anticancer	Various solid tumors (lung, ovarian, leukemia)	Induces oxidative stress, inhibits cancer stem-like cells	3 6 7 10 14
Iron Disorders	Hereditary hemochromatosis	Upregulates hepcidin, reduces iron overload	2
Steroid-dependent Asthma	Chronic asthma requiring oral steroids	Steroid-sparing, reduces corticosteroid needs	8 9

Table 1: Key Clinical and Investigational Uses of Auranofin

Rheumatoid Arthritis

Auranofin remains most widely recognized as a disease-modifying anti-rheumatic drug (DMARD). It is used for patients with active, progressive rheumatoid arthritis, especially those intolerant or unresponsive to other DMARDs. It exerts its effects through immunomodulation and possibly by altering lysosomal enzyme activity, resulting in reduced inflammation and joint damage progression 3 12.

Infectious Diseases

Antibacterial Activity

Recent studies have revealed auranofin’s potent activity against a variety of Gram-positive bacteria, including drug-resistant strains of Staphylococcus aureus and Enterococcus species, as well as Mycobacterium tuberculosis. Its unique mechanism—targeting thioredoxin reductase—sets it apart from traditional antibiotics, making it effective where other agents may fail 1.

Antiparasitic and Antifungal Effects

Auranofin is effective against protozoan parasites such as Entamoeba histolytica and Giardia intestinalis, including metronidazole-resistant strains. Animal and early human clinical trials support its safety and efficacy for these indications 4. Additionally, it shows broad-spectrum antifungal activity, disrupting mitochondrial protein import in fungi and reducing biofilm viability, especially against Candida and Cryptococcus species 5.

Cancer Therapy

Preclinical and early clinical studies suggest that auranofin’s inhibition of thioredoxin reductase increases oxidative stress in cancer cells, potentially suppressing tumor growth. It is under investigation for various cancers, especially lung, ovarian, and leukemia, and may enhance the effects of other chemotherapeutics by targeting cancer stem-like cells 3 6 7 10 14.

Other Investigational Uses

• Iron Overload Disorders: Auranofin has been found to upregulate hepcidin, the key regulator of iron metabolism, thereby reducing iron overload in hereditary hemochromatosis models 2.
• Steroid-dependent Asthma: Clinical trials demonstrate a steroid-sparing effect in patients with chronic asthma requiring oral corticosteroids, allowing for lower doses and reduced steroid-related side effects 8 9.

Dosage of Auranofin

Understanding the optimal dosing of auranofin is critical, as it varies based on indication and patient characteristics. Most clinical experience comes from its use in rheumatoid arthritis, though investigational uses often employ different regimens.

Indication	Typical Dosage	Route	Sources
Rheumatoid Arthritis	6 mg/day (3 mg twice daily)	Oral	4 12
Asthma (Steroid-sparing)	3 mg twice daily	Oral	8 9
Antiparasitic (Trial)	6 mg/day for 7 days	Oral	4
Investigational Cancer	Variable (preclinical)	Oral or i.p.	6 7 10 14
Iron Overload Disorders	5 mg/kg (animal studies)	Oral	2

Table 2: Representative Dosage Regimens for Auranofin

Standard Dosing in Rheumatoid Arthritis

The most established dosing is 6 mg per day, given as 3 mg twice daily. This oral regimen provides disease-modifying effects with manageable side effects for most patients 12.

Dosage in Other Conditions

• Asthma: Clinical trials in steroid-dependent asthma used the same 6 mg/day split into two doses 8 9.
• Parasitic Infections: Phase I trials for E. histolytica and Giardia used 6 mg/day for 7 days, mirroring the rheumatoid arthritis regimen 4.
• Cancer and Iron Disorders: Doses in preclinical studies vary widely, with animal models for cancer and iron overload employing higher mg/kg doses to achieve desired therapeutic effects 2 6 7 10 14.

Considerations for Dose Adjustment

• Duration: For chronic conditions (e.g., rheumatoid arthritis), treatment is long-term. For infections, therapy is typically short-term.
• Side Effects: Dose reduction or discontinuation may be required in case of significant side effects 12.
• Patient Factors: Age, renal and hepatic function, and concurrent medications may influence dosing decisions.

Side Effects of Auranofin

While generally well-tolerated, auranofin can cause a range of side effects. Understanding these is essential for safe use, particularly as its indications expand.

Side Effect	Frequency/Severity	Notes	Sources
Diarrhea	Common, may be dose-limiting	Often mild to moderate, may require dose reduction	12
Skin Rash/Pruritus	Common	Sometimes troublesome, may lead to discontinuation	12
Thrombocytopenia	Uncommon but serious	Requires monitoring	12
Proteinuria	Uncommon but serious	Monitor renal function	12
Gastrointestinal	Most frequent overall	Nausea, abdominal pain	4 12
Mild anemia	Observed	May be due to eryptosis (RBC death)	11
Exacerbation of eczema	Notable in asthma trials	Monitor in at-risk patients	9
Mild, reversible adverse events	~47% in trials	All mild, resolved spontaneously	4

Table 3: Common and Serious Side Effects of Auranofin

Gastrointestinal and Skin Reactions

Diarrhea is the most frequently reported side effect and can be dose-limiting. Skin reactions, including rash and pruritus, are also common. While these are generally milder compared to injectable gold compounds, they may require dose adjustment or discontinuation 12.

Hematologic and Renal Effects

More serious but less common side effects include thrombocytopenia (low platelet count) and proteinuria (protein in urine), both of which may necessitate stopping the drug and close monitoring of blood counts and renal function 12.

Other Observed Reactions

• Mild Anemia: Linked to stimulation of eryptosis, or programmed red blood cell death, possibly due to increased oxidative stress 11.
• Eczema Flare: Exacerbation of constitutional eczema was noted in some asthma patients 9.
• General Tolerability: In phase I trials for parasitic diseases, nearly half of subjects reported mild, self-limited adverse events 4.

Management of Side Effects

• Most gastrointestinal and skin reactions resolve with dose reduction or temporary withdrawal.
• Regular laboratory monitoring is recommended to detect serious hematological or renal effects early 12.

Interactions of Auranofin

Auranofin’s unique chemistry and mechanism of action set it apart from many other drugs, but they also introduce the potential for interactions, especially with agents affecting redox balance or with high protein binding.

Interaction Type	Description	Clinical Impact	Sources
Protein Binding	Binds to serum proteins	Decreases cellular uptake and efficacy	13
Antioxidants	NAC can reverse effects	May reduce efficacy in cancer therapy	10
Other Immunosuppressants	Potential additive effects	Increased risk of infection or toxicity	12
Drugs affecting redox	May have synergy or antagonism	Caution with other oxidative stress-inducing agents	3 10

Table 4: Notable Auranofin Drug and Biochemical Interactions

Protein Binding and Cellular Uptake

Auranofin binds extensively to serum proteins such as albumin, which can decrease the amount of drug available to enter cells and exert its effects. This is particularly relevant for its anticancer and anti-inflammatory actions 13.

Redox Modulators

Since auranofin acts primarily by increasing oxidative stress (through inhibition of thioredoxin reductase), drugs or supplements that modulate redox status can influence its effectiveness. For example, the antioxidant N-acetylcysteine (NAC) can reverse auranofin’s depletion of cancer stem-like cells, potentially reducing its anticancer activity 10.

Immunosuppressive Agents

Concurrent use with other immunosuppressive drugs may increase the risk of infections or toxicity, necessitating careful monitoring 12.

Synergistic and Antagonistic Effects

• Synergy: Auranofin may enhance the efficacy of certain chemotherapeutic agents (like adriamycin) by impairing drug efflux pumps in cancer cells 10.
• Antagonism: Use with antioxidants (e.g., vitamin E, NAC) could counteract its intended mechanism in cancer therapy 10.

Clinical Considerations

• Always assess the patient’s medication list for potential interactions.
• Monitor for increased toxicity or loss of efficacy when introducing new medications.

Conclusion

Auranofin is a versatile and promising agent whose traditional role in rheumatoid arthritis is expanding to encompass infectious diseases, cancer, and metabolic disorders. As research into its mechanisms and applications continues, clinicians and patients should be aware of its dosing parameters, potential side effects, and notable drug interactions.

Key points:

• Broad Utility: Used in rheumatology, and under active investigation for antibacterial, antiparasitic, antifungal, anticancer, and iron-regulating effects [1-10,12].
• Dosing: Well-established for rheumatoid arthritis (6 mg/day oral), with similar regimens used in trials for other conditions 4 8 9 12.
• Side Effects: Most common are gastrointestinal and skin reactions; serious hematologic and renal effects are rare but require monitoring 4 9 11 12.
• Drug Interactions: Protein binding and redox modulation are key concerns; potential for both synergy and antagonism with other agents 3 10 12 13.
• Ongoing Research: New uses in infectious disease, oncology, and metabolic disorders hold promise for future therapeutic advances.

Auranofin’s evolving profile exemplifies the potential of drug repurposing to address unmet medical needs across a spectrum of diseases. As always, therapeutic use should be guided by careful patient assessment, monitoring, and awareness of emerging evidence.