Rheumatoid Arthritis 
Aurothioglucose and gold sodium thiomalate are used in the management of rheumatoid arthritis in adults or juvenile rheumatoid arthritis in children whose symptoms progress despite an adequate regimen of nonsteroidal anti-inflammatory agents (NSAIAs). Aurothioglucose and gold sodium thiomalate are disease-modifying antirheumatic drugs (DMARDs) that can be used when DMARD therapy is appropriate. (For further information on the treatment of rheumatoid arthritis, see Uses: Rheumatoid Arthritis, in Methotrexate 10:00.) Administration of aurothioglucose or gold sodium thiomalate alone is not a complete treatment for rheumatoid arthritis, and the drugs should only be used as one part of a comprehensive treatment program, including non-drug therapies such as rest and physical therapy. Most patients with active rheumatoid arthritis will show some benefit from therapy with gold compounds, including aurothioglucose and gold sodium thiomalate, and favorable results may be most likely when chrysotherapy is administered in patients with active synovitis, particularly in the early stage. There is no substantial evidence that gold compounds, including aurothioglucose and gold sodium thiomalate, permanently arrest or reverse the underlying disease process, although the drugs may slow its progression. Parenteral gold compounds appear to be as effective as or slightly more effective but more toxic than the oral gold compound auranofin.
Parenteral gold compounds are generally effective in decreasing the number of painful and/or tender and swollen joints, the duration of morning stiffness, the articular index, rheumatoid activity index, and erythrocyte sedimentation rate, and in increasing grip strength. Parenteral gold compounds do not possess direct analgesic activity, but as a result of anti-inflammatory and antiarthritic effects, therapy with the drugs generally results in a reduction of disease-associated pain. There is some evidence from radiographic studies suggesting that parenteral gold compounds may slow or arrest the progression of joint space narrowing and/or bone erosion associated with rheumatoid arthritis; further well-designed studies are needed to conclusively determine whether the drugs can reduce the severity or rate of progression of joint space narrowing and bone erosion associated with the disease. When damage to cartilage and bone has already occurred, therapy with gold compounds, including aurothioglucose and gold sodium thiomalate, cannot reverse structural damage to joints caused by previous disease.
Results of numerous comparative clinical studies suggest that gold sodium thiomalate or aurothioglucose is as effective as or slightly more effective but more toxic than auranofin in the management of active rheumatoid arthritis. While most comparative studies have not shown a substantial difference in efficacy between these parenteral gold compounds and auranofin, the therapeutic effects generally tended to be slightly more pronounced and, in some studies, occurred sooner with the parenteral gold compounds. Patients receiving a parenteral gold compound generally discontinue therapy less frequently because of an inadequate or poor therapeutic response (less than 5% of patients), but substantially more often because of adverse effects (about 25-35% of patients), than patients receiving auranofin. Further studies are needed to more clearly define the relative efficacies of parenteral gold compounds and auranofin and the adverse effect profile of auranofin, particularly with long-term therapy. Because it offers the convenience of oral administration, auranofin may be preferred to a parenteral gold compound in some patients (e.g., those who dislike injections or for whom weekly injections and/or visits to the physician are inconvenient); however, in other patients, including those in whom compliance with a daily dosing regimen may be a problem, therapy with a parenteral gold compound may be preferred. Because auranofin may be slightly less effective, some clinicians prefer a parenteral gold compound in patients with severe or rapidly progressive disease. Auranofin appears to be capable of sustaining a therapeutic response for at least 6-12 months in many patients transferred from effective therapy with a parenteral gold compound; however, some patients effectively treated with a parenteral gold compound may experience worsening of disease (particularly those whose disease was more active at the initiation of chrysotherapy) or may not respond to auranofin following the transfer. Additional studies are needed to further evaluate the efficacy of parenteral gold compounds in patients who have an adequate therapeutic response to auranofin and vice versa. Data currently are limited, but some patients who have an inadequate therapeutic response or an adverse reaction to a parenteral gold compound and/or penicillamine may respond to and tolerate auranofin, and some patients who have an inadequate response to or do not tolerate auranofin may respond to and tolerate a parenteral gold compound; further studies are needed. The safety and efficacy of a parenteral gold compound in patients who have adverse reactions to auranofin and vice versa remain to be more clearly established. Many clinicians, however, would consider cautious administration of auranofin to patients who have had mild to moderate adverse reactions (e.g., adverse mucocutaneous reactions) to a parenteral gold compound, but not to those who have had adverse hematologic reactions or potentially fatal adverse reactions.
Comparative clinical studies to date indicate that parenteral gold compounds are at least as effective as antimalarial agents and penicillamine in the management of progressive rheumatoid arthritis. Gold sodium thiomalate has been administered intra-articularly† in the treatment of rheumatoid arthritis. Although a limited number of patients appeared to benefit from this treatment, more study is needed before intra-articular administration of the drug can be recommended.
Other Uses
Parenteral gold compounds may be beneficial in the management of psoriatic arthritis† or Felty's syndrome†. In the past, parenteral gold compounds have been used in the treatment of discoid (nondisseminated) lupus erythematosus†; gold compounds are generally considered to be contraindicated in patients with systemic lupus erythematosus. Gold compounds are thought to be ineffective in ankylosing spondylitis, Reiter's syndrome, or other forms of arthritis.
Parenteral gold compounds have been used with beneficial effects in the treatment of palindromic rheumatism†; however, these drugs should not be used for other forms of rheumatism. Parenteral gold compounds have been used successfully in the treatment of pemphigus†. Although a systemically administered corticosteroid is the drug of choice in the management of pemphigus, gold compounds may prove to be a reasonable alternative to long-term corticosteroid therapy.
Administration
Aurothioglucose and gold sodium thiomalate are administered only by IM injection, preferably intragluteally. The drugs should not be administered IV . Because of the possibility of anaphylactic or vasomotor (nitritoid) reactions, it is recommended that patients be lying down when the drugs are administered, that they remain recumbent for 10 minutes after administration, and that they be observed for at least 15 minutes after the drugs are given.
Aurothioglucose
Aurothioglucose is injected IM, usually deep into the upper outer quadrant of the gluteal region using a 1½-inch (2-inch for obese patients) 18- or 20-gauge needle. Aurothioglucose must not be injected IV. Before withdrawing the dose, the vial should be thoroughly shaken to obtain a uniform suspension. Immersing the vial in warm water to heat the suspension to body temperature will facilitate its withdrawal from the vial. The needle and syringe used to obtain the dose must be dry.
Gold Sodium Thiomalate
Gold sodium thiomalate is injected IM, usually deep into the upper outer quadrant of the gluteal region.
Dosage
Optimum dosage schedules for parenteral gold compounds have not been conclusively established. Therapeutic effects occur slowly and at least 6-8 weeks of therapy are usually required before any improvement is noted with parenteral gold therapy. The optimum duration of treatment in patients who benefit from chrysotherapy has not been established, but chrysotherapy is generally continued as long as clinical improvement is evident and adverse effects do not require discontinuance of treatment.
Aurothioglucose
Initially, aurothioglucose is given at weekly intervals. The usual initial adult dose is 10 mg followed by 25 mg for the second and third doses, then 50 mg weekly until 0.8-1 g has been administered. If the patient has improved and no signs of gold toxicity are evident, 25-50 mg may be given at 3- to 4-week intervals indefinitely. If no substantial improvement is evident after a total of 1 g of aurothioglucose has been administered, the need for parenteral gold therapy should be reevaluated.
Children 6-12 years of age may receive one-fourth of the usual adult dose of aurothioglucose, not to exceed 25 mg per dose. Alternatively, children may be given 1 mg/kg weekly for 20 weeks.
Gold Sodium Thiomalate
Gold sodium thiomalate is administered IM at weekly intervals initially. The usual initial adult dose is 10 mg followed by 25 mg for the second dose, then 25-50 mg weekly until gold toxicity or substantial clinical improvement occurs, or a cumulative dose of 1 g has been administered. If substantial clinical improvement occurs before a total dose of 1 g has been administered, the dose may be decreased or the interval between injections increased as with maintenance therapy. The usual maintenance dosage is 25-50 mg every 2 weeks for 2-20 weeks. If the clinical course of the patient remains stable, 25-50 mg may be given every third and subsequently every fourth week indefinitely. Some patients may require maintenance doses at 1- to 3-week intervals. If arthritis exacerbates during maintenance therapy, weekly doses may be resumed temporarily until disease activity is suppressed. If no substantial improvement is evident after a total dose of 1 g has been administered, the patient may be considered unresponsive and gold sodium thiomalate therapy discontinued. Alternatively, a dose of 25-50 mg may be continued for approximately 10 additional weeks, or the dose may be increased by increments of 10 mg every 1-4 weeks, not to exceed 100 mg in a single dose. If substantial clinical improvement occurs with an alternative regimen, the usual maintenance therapy should be initiated; if gold toxicity or no substantial improvement occurs, gold sodium thiomalate therapy should be discontinued. When gold sodium thiomalate therapy is reinstituted following resolution of a mild adverse reaction, a reduced dosage schedule should be used. If an initial test dose of 5 mg is well tolerated, dosage may be increased by 5- to 10-mg increments at weekly to monthly intervals until a dose of 25-50 mg is reached.
The usual dose of gold sodium thiomalate for children is based on the weight of the child and is proportional to the adult dose. The maximum single dose for children younger than 12 years of age is 50 mg. After an initial test dose of 10 mg, one dosage regimen recommended for children is 1 mg/kg per week. Alternatively, a dose of 2.5-5 mg may be given the first and second weeks followed by 1 mg/kg per week thereafter. If a good response occurs, this dosage may be administered at 3- to 4-week intervals indefinitely. The usual administration guidelines for adults also apply to children.
When gold sodium thiomalate was used in the treatment of palindromic rheumatism†, weekly doses of 10-50 mg were given until a total of 1 g was administered. In the management of pemphigus†, an initial dose of 10 mg of gold sodium thiomalate was given, followed by a 25-mg dose the second week, and then 50 mg weekly until corticosteroids were eliminated from the drug regimen; a maintenance dosage of 25-50 mg every 2 weeks was then given.
Aurothioglucose and gold sodium thiomalate appear to be more toxic and less well tolerated than the oral gold compound, auranofin, generally resulting in substantially more withdrawals from therapy because of adverse reactions (about 25-35% of patients); however, additional experience is needed to more fully characterize the adverse effect profile of auranofin, particularly with long-term therapy. Parenteral gold compounds produce fewer adverse GI effects, including those severe enough to require discontinuance of therapy, than auranofin, but more frequent and severe adverse mucocutaneous (and possibly renal) effects than auranofin. The overall difference in toxicity-related rates of withdrawal from therapy between parenteral gold compounds and auranofin results principally from the increased frequency and severity of adverse mucocutaneous effects associated with parenteral gold compounds. There is some evidence suggesting that aurothioglucose may be less toxic than gold sodium thiomalate.
Most adverse reactions to parenteral gold compounds occur during the second or third month of treatment after a total of 250-500 mg of the drug has been given, but they may occur at any time throughout therapy and very rarely for several months after gold therapy has been discontinued. Although the incidence of adverse effects with parenteral gold compounds is high, most reactions respond favorably to discontinuance of the drugs; however, severe reactions may require specific treatment. The incidence of severe reactions to gold compounds is low, with such reactions usually occurring when therapy is continued despite the occurrence of less serious signs and symptoms of gold toxicity. Patients with HLA-DR locus histocompatibility antigen DR3 appear to have a genetic predisposition to develop adverse effects, including specific adverse reactions (e.g., proteinuria), during chrysotherapy. Although not clearly established, there is also some evidence that gold-induced adverse effects, including specific adverse reactions (e.g., mucocutaneous effects, thrombocytopenia), may be immunologically mediated.
Mucocutaneous Effects
The most frequent adverse effects of parenteral gold therapy involve skin and mucous membranes. Cutaneous reactions may range from simple erythema to severe exfoliative dermatitis and may include urticaria, erythema nodosum, and papular, vesicular, or lichenoid lesions. A gray-to-blue pigmentation (chrysiasis) may also occur in skin and mucous membranes. Exfoliative dermatitis may lead to alopecia, which may persist for 2-3 years, and shedding of nails. Gold-induced exfoliative dermatitis has resulted in a few fatalities. Gold-induced dermatitis may be aggravated by exposure to sunlight or an actinic rash may develop. Pruritus often occurs before rash becomes apparent and should be considered a warning signal of an impending cutaneous reaction.
Mucous membrane reactions include stomatitis, gingivitis and glossitis (sometimes diffuse), pharyngitis, tracheitis, and vaginitis. Shallow ulcers on the buccal membranes, palate, pharynx, or borders of the tongue may occur, sometimes concurrently with dermatitis. A metallic taste may precede oral mucous membrane reactions and should be considered a warning signal of impending gold toxicity.
Skin and mucous membrane reactions induced by parenteral gold compounds require interruption of therapy, at least temporarily. (See Cautions: Precautions and Contraindications.) Moderately severe skin and mucous membrane reactions may be relieved by topical corticosteroids, oral antihistamines, and/or soothing or anesthetic topical preparations when indicated. Severe or generalized gold compound-induced dermatitis or stomatitis may require systemic corticosteroid therapy (e.g., oral prednisone 10-40 mg daily in divided doses).
Hematologic Effects
One of the most serious toxic effects of parenteral gold compounds is hematologic toxicity. Although severe blood dyscrasias occur rarely, they may be fatal and have included hemorrhagic diathesis, thrombocytopenia with or without purpura, hypoplastic or aplastic anemia, agranulocytosis, leukopenia, and granulocytopenia. Eosinophilia frequently precedes or accompanies severe parenteral gold toxicity and may be a useful parameter for monitoring parenteral gold therapy. When thrombocytopenia occurs, most patients respond to discontinuance of parenteral gold therapy and administration of corticosteroids (e.g., prednisone 60 mg daily for several weeks or months). Platelet transfusions may be required if bleeding occurs. Some patients may also require administration of dimercaprol.
Renal and Hepatic Effects
Parenteral gold compounds may be nephrotoxic and hepatotoxic, producing a nephrotic syndrome, glomerulitis with hematuria, and toxic hepatitis with jaundice. These renal or hepatic reactions are usually mild and reversible; however, some fatalities have occurred. Transient proteinuria may occur in as many as 50% of patients treated with parenteral gold compounds. Gold-induced adverse renal effects are usually relatively mild and completely reversible if recognized early and chrysotherapy is discontinued; however, adverse renal effects may become severe and chronic if chrysotherapy is continued. If clinically important proteinuria or microscopic hematuria occurs during parenteral gold therapy, the parenteral gold compound and other therapies with the potential for causing these adverse renal effects should be promptly discontinued. (See Cautions: Precautions and Contraindications.) High-Dose corticosteroids may be of benefit for some cases of severe or progressive gold-induced adverse renal effects, but are usually not necessary. Nephrotic syndrome often responds to oral corticosteroids.
Jaundice, with or without cholestasis, and hepatitis have been attributed to parenteral gold therapy.
Sensitivity Reactions
Rarely, anaphylactic shock, syncope, bradycardia, thickening of the tongue, difficulty in swallowing and breathing, and angioedema may occur immediately to 10 minutes after administration of a parenteral gold compound. If such a reaction occurs, parenteral chrysotherapy should be discontinued. Occasionally, arthralgia occurs for 1 or 2 days after injection of a gold compound and usually subsides after the first few injections. Transient vasomotor (nitritoid) reactions consisting of flushing, fainting, dizziness, sweating, nausea, vomiting, pounding headache, blurred vision, weakness, and malaise have occurred in some patients. Vasomotor reactions are more frightening than harmful and do not usually require discontinuance of therapy. Although vasomotor reactions can occur with either of the currently available parenteral gold compounds, the reactions have occurred principally with gold sodium thiomalate. Patients who experience vasomotor reactions with gold sodium thiomalate may tolerate aurothioglucose.
GI Effects
Adverse GI effects rarely develop in association with parenteral gold therapy; nausea and vomiting, anorexia, diarrhea (sometimes persistent), abdominal cramps, and colic have been reported. Gastritis and proctitis may also occur. Ulcerative colitis, which can be severe or even fatal, has been reported rarely. Eosinophilic enterocolitis also has been reported, and limited data suggest that orally administered cromolyn sodium may be beneficial in the management of such enterocolitis.
Ocular Effects
Ocular reactions to parenteral gold compounds have been reported rarely and have included conjunctivitis, iritis, and corneal ulcers. Gold frequently is deposited in the cornea during parenteral chrysotherapy but does not cause visual disturbances.
Other Adverse Effects
Other adverse effects which have been associated with parenteral chrysotherapy are headache; fever; partial or complete hair loss; pulmonary infiltration; pulmonary injury manifested as interstitial pneumonitis and fibrosis; and “gold” bronchitis. Rarely, peripheral and central nervous system complications have occurred with parenteral chrysotherapy. Peripheral neuropathy, with or without fasciculations; sensorimotor effects including polyradiculoneuropathy (Guillain-Barré syndrome); and elevated CSF protein concentration have been reported. Adverse CNS effects have included confusion, hallucinations, EEG abnormalities, and seizures. Adverse nervous system effects usually resolved following discontinuance of chrysotherapy.
Precautions and Contraindications
Aurothioglucose and gold sodium thiomalate should be administered only to carefully selected patients who are under constant supervision of a physician experienced with chrysotherapy and thoroughly familiar with the toxicity and benefits of the drugs. The fact that gold compounds can produce severe toxic reactions should always be kept in mind. To minimize the toxicity associated with chrysotherapy, emphasis should be placed on careful clinical and laboratory monitoring and early detection of adverse reactions. Medical conditions that might affect the signs or symptoms used to detect aurothioglucose or gold sodium thiomalate toxicity should be adequately controlled before therapy with the drugs is initiated. When deciding whether to use aurothioglucose or gold sodium thiomalate in candidates for chrysotherapy, physicians should consider the relative benefits and risks of parenteral gold compounds and auranofin. (See Uses: Rheumatoid Arthritis.)
Before initiation of aurothioglucose or gold sodium thiomalate therapy, the possibility of adverse reactions should be explained to patients. Patients should be informed to promptly report any sign or symptom of possible gold toxicity, particularly pruritus, rash, stomatitis, indigestion, or metallic taste, to their physician. Patients should also be advised to contact their physician promptly if bruising, unusual or prolonged bleeding, or persistent diarrhea occurs. In addition, patients should be questioned regarding these signs and symptoms before each dose of parenteral chrysotherapy is administered. Since photosensitivity reactions may develop or gold-induced dermatitis may be aggravated with exposure to sunlight or artificial ultraviolet light, patients should also be cautioned to minimize such exposure.
Before parenteral gold therapy is initiated, a complete blood cell count with differential, platelet count, a hemoglobin concentration, urinalysis, and renal and liver function tests should be performed to establish a baseline and identify any preexisting conditions. During parenteral chrysotherapy, urinalysis should be performed frequently, and before each dose. Complete blood cell counts and platelet counts should be performed regularly during parenteral chrysotherapy at 2- to 4-week intervals or before every other injection. Physicians should carefully review the results of laboratory tests to determine if an interruption of parenteral chrysotherapy is necessary. Signs of possible gold toxicity include a rapid decrease in hemoglobin concentration, leukocyte count less than 4000/mm3, granulocyte count less than 1500/mm3, eosinophilia greater than 5%, a decrease in platelet count to less than 100,000/mm3, proteinuria, hematuria, pruritus, rash, stomatitis, and persistent diarrhea. If a precipitous decline in platelet count, a platelet count less than 100,000/mm3, or signs and/or symptoms suggestive of thrombocytopenia (e.g., purpura, ecchymoses, petechiae, bleeding gums) occur during parenteral gold therapy, parenteral gold therapy and other therapies with the potential for causing thrombocytopenia should be immediately discontinued and additional platelet counts should be subsequently obtained. Parenteral chrysotherapy should not be resumed unless the thrombocytopenia resolves and further studies confirm it was not caused by chrysotherapy. If clinically important proteinuria or microscopic hematuria occurs during parenteral gold therapy, parenteral gold therapy and other therapies with the potential for causing these adverse renal effects should be promptly discontinued. Parenteral chrysotherapy generally should not be resumed unless the adverse renal effects resolve and further studies confirm that they were not caused by chrysotherapy; however, if the reactions were not severe and/or have adequately resolved, cautious rechallenge with parenteral gold therapy may be attempted if considered necessary because of the patient's clinical condition. Any skin eruption, especially if pruritic, that develops during parenteral gold therapy should be considered a reaction to gold until proven otherwise. When rash and/or pruritus, or stomatitis occurs in patients receiving parenteral gold therapy, therapy with the drug should be discontinued. Following resolution of mild or moderate adverse mucocutaneous effects, cautious reinstitution of parenteral gold therapy may be attempted, in smaller doses, 2-3 weeks after the reaction fully subsides; the majority of patients tolerate resumption of parenteral gold therapy initiated with a reduced dosage schedule, but those who experience recurrent reactions tend to have reactions similar to those manifested initially. If other signs of possible gold toxicity (e.g., leukocyte count less than 4000/mm3) occur during parenteral gold therapy, therapy with the drug should generally be discontinued until further studies confirm that the adverse effect was not gold induced. Parenteral gold therapy should not be resumed in patients who have had a severe or idiosyncratic reaction to gold.
When severe reactions to parenteral gold compounds occur, recovery may be facilitated by the use of corticosteroids, dimercaprol, or penicillamine. For the management of severe renal, hematologic, pulmonary, or enterocolitic reactions to gold compounds, high doses of systemic corticosteroids (e.g., prednisone 40-100 mg daily in divided doses) are recommended by the manufacturers; the optimum duration of corticosteroid therapy is variable, but may be many months when these adverse effects are unusually severe or progressive. When high-dose corticosteroid therapy is ineffective or substantial adverse reactions to corticosteroid therapy occur, a chelating agent (e.g., dimercaprol) may be used to enhance the elimination of gold; corticosteroids and a chelating agent may be used concomitantly.
Parenteral gold compounds should be administered with extreme caution, if at all, to patients with a history of blood dyscrasias, particularly if caused by drug sensitivity. Parenteral gold compounds should also be administered with extreme caution, if at all, to patients with marked hypertension, compromised cerebral or cardiovascular circulation, rash, a history of renal or hepatic disease, or allergy or hypersensitivity to drugs.
Most patients who have received parenteral gold therapy have received a nonsteroidal anti-inflammatory agent or corticosteroid therapy concomitantly without unusual toxicity. The safety of concomitant administration of parenteral gold compounds and antimalarials (e.g., hydroxychloroquine), penicillamine, or immunosuppressive agents (e.g., azathioprine, cyclophosphamide, methotrexate) has not been established. Concomitant administration of gold compounds with antimalarials, immunosuppressive agents, penicillamine, or phenylbutazone is generally contraindicated because of the drugs' potential to cause blood dyscrasias or other mutual, potentially severe adverse effects (e.g., proteinuria, dermatitis).
Parenteral gold compounds are contraindicated in patients with a history of severe toxicity resulting from previous exposure to gold or other heavy metals. The drugs are usually contraindicated in patients with impaired renal or hepatic function, colitis, or a history of hepatitis or exfoliative dermatitis. Parenteral gold compounds should not be administered to severely debilitated patients or to patients with urticaria, eczema, uncontrolled diabetes mellitus, uncontrolled congestive heart failure, hemorrhagic conditions, agranulocytosis or other severe hematologic disorders, or systemic lupus erythematosus, or those who have recently received radiation therapy. Some sources indicate that parenteral gold compounds are contraindicated in patients with Sjögren's syndrome; however, some data indicate that these patients can tolerate parenteral gold compounds and that chrysotherapy should not be withheld from patients with Sjögren's syndrome. Therapy with the respective preparation is contraindicated in patients with known hypersensitivity to any component in the specific formulation.
Pediatric Precautions
Safety and efficacy of parenteral gold compounds in children younger than 6 years of age have not been established.
Pregnancy and Lactation
Pregnancy
Reproduction studies in rats and rabbits have shown gold sodium thiomalate to have teratogenic effects when given in doses 140 and 175 times, respectively, the usual human dose. In pregnant rats receiving a subcutaneous dosage of 25 mg/kg daily from days 6-15 of gestation, fetal hydrocephalus and microphthalmia were observed, and in pregnant rabbits receiving a subcutaneous dosage of 20-45 mg/kg daily from days 6-18 of gestation, fetal limb defects and gastroschisis were observed.
There are no adequate and controlled studies to date using aurothioglucose or gold sodium thiomalate in pregnant women, but clinical experience to date has not revealed substantial evidence of adverse effects on the fetus. Women of childbearing potential should be warned of the potential risks of parenteral gold therapy during pregnancy. Women of childbearing potential in whom parenteral gold therapy is considered should be counseled about methods of birth control and advised not to become pregnant while receiving the drug; these women should be advised to inform their physician if pregnancy occurs or is suspected during parenteral gold therapy. The prolonged elimination of gold from the body after discontinuance of chrysotherapy should be considered when a woman of childbearing potential receiving chrysotherapy plans to become pregnant. Chrysotherapy is usually not administered to pregnant women and is usually discontinued if pregnancy occurs; however, chrysotherapy may be used with caution during pregnancy when the potential benefits to the mother justify the possible risks to the fetus.
Lactation
Small amounts of gold have been shown to be distributed into milk in women receiving aurothioglucose or gold sodium thiomalate and to have been absorbed in their nursing infants. It has been suggested that this may be the cause of some unexplained adverse effects (e.g., rash, nephritis, hepatitis, hematologic aberrations) in some nursing infants of women treated with parenteral gold compounds. Because of the potential for serious adverse reactions from parenteral gold compounds in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the nursing woman. The slow elimination of gold from the body after discontinuance of chrysotherapy should also be considered.
Laboratory Test Interferences
Serum concentrations of gold achieved during parenteral chrysotherapy interfere with the measurement of serum protein-bound iodine by the chloric acid digestion method and possibly other methods, and this effect may persist for several weeks after therapy has been discontinued.
Pharmacology
Anti-inflammatory, Antiarthritic, and Immunomodulating Effects
Like other gold compounds, aurothioglucose and gold sodium thiomalate exhibit anti-inflammatory, antiarthritic, and immunomodulating effects. The exact mechanism(s) of action of gold compounds, including these parenteral gold compounds, in the treatment of rheumatoid arthritis has not been clearly established, in part because the pharmacologic effects of the drugs and the etiology of the disease are complex. The strong affinity of gold for sulfur and the inhibitory effect of parenteral gold compounds on pyruvic dehydrogenase suggest that their effects may result from inhibition of sulfhydryl systems in such a way as to alter cellular metabolism. In patients with rheumatoid arthritis, parenteral gold compounds may act by altering function of other enzymes, by inhibiting lysosomal enzymes, by suppressing phagocytic activity of macrophages and polymorphonuclear leukocytes, or by altering the immune response. It is not definitely known whether nonprotein-bound gold, protein-bound gold, or the gold associated with cells is the pharmacologically active moiety of gold compounds. Some data suggest that the active moiety is nonprotein-bound gold. The pharmacologic effects of aurothioglucose, gold sodium thiomalate, and other gold compounds (e.g., auranofin) are generally qualitatively similar, but some effects of the drugs differ quantitatively and/or qualitatively; however, it remains to be determined whether such differences are clinically important. Similarly, much of the information on the potential mechanism(s) of action of gold compounds is based on in vitro studies, and the relevance of the results to in vivo activity of the drugs and any potential clinical importance remain to be more clearly defined.
In vitro, gold has marked anti-infective properties, but gold compounds do not have any therapeutic effect in clinical infections. In animals, parenteral gold compounds can suppress or prevent arthritis and synovitis induced by infections and/or chemical agents. In rats, parenteral gold compounds alter the properties of collagen and inhibit lysosomal enzymes and the formation of glucosamine-6-phosphate in connective tissue. Parenteral gold compounds also suppress the anaphylactic release of histamine, moderately suppress cellular immunity and, like other antirheumatic drugs, decrease the binding of tryptophan to plasma proteins. In vitro, parenteral gold compounds have also been shown to inhibit prostaglandin synthesis, inactivate C1 in the complement system, and inhibit the thermal aggregation of human gamma globulin.
Pharmacokinetics
Absorption
Gold sodium thiomalate solutions are rapidly absorbed following IM injection, with peak serum concentrations occurring in 3-6 hours. Following IM administration as a suspension in oil, aurothioglucose is absorbed more slowly and irregularly. After chronic administration of usual therapeutic doses of parenteral gold compounds, serum concentrations have been reported to range from 1-10 mcg/mL. With weekly injections, it usually takes 1-2 months for the mean serum concentration to reach a plateau. Mean steady-state blood gold concentrations attained with parenteral gold compounds are substantially higher than those attained with auranofin. The onset and duration of action of parenteral gold compounds are difficult to quantify since the beneficial effects of these drugs may occur only after several weeks or months of therapy and may persist long after chrysotherapy has been discontinued.
Most studies have shown that blood, serum, or total body gold concentrations attained with parenteral gold compounds do not correlate well with therapeutic effects or toxicity. It is not clear whether the concentration of gold associated with blood cells in some patients during parenteral chrysotherapy is correlated with therapeutic efficacy or toxicity.
Distribution
There is limited information regarding distribution of gold into human body tissues and fluids during parenteral chrysotherapy. Since substantial amounts of gold are retained in the body during long-term therapy with parenteral gold compounds, tissue gold concentrations achieved with parenteral chrysotherapy are likely to be substantially higher than those attained with auranofin therapy, and this is supported by the results of distribution studies in animals and limited human data to date. The apparently higher tissue concentrations of gold may account in part for the tendency of some adverse effects of parenteral gold compounds to occur more frequently and be more severe than those of auranofin.
Animal studies and limited human studies show that absorbed gold is concentrated in the reticuloendothelial cells of the lymph nodes, bone marrow, kidneys, liver, and spleen but is also widely distributed throughout body tissues. Synovial fluid gold concentrations in rheumatoid arthritis patients receiving parenteral gold compounds are much higher than those in patients receiving auranofin, but the ratio of blood-to-synovial fluid gold concentrations during parenteral gold therapy is similar to that during auranofin therapy. During parenteral chrysotherapy, the concentration of gold in synovial fluid is about one-half that in plasma. Arthritic joints contain 2-2.5 times as much gold as uninvolved joints. It has been reported that gold does not cross the blood-brain barrier during parenteral therapy. In contrast to other heavy metals, gold has little affinity for keratinous tissues (hair, nails, and skin). Gold is distributed into the lens and cornea during parenteral chrysotherapy and some accumulation can occur. Following a single dose of a parenteral gold compound in animals, gold appears to be distributed principally within organelles (e.g., lysosomes, mitochondria) rather than within the cytosol. Within the cytosol, gold is bound in part to metallothionein(s).
In contrast to the distribution of gold in blood during auranofin therapy, the gold in blood during therapy with parenteral gold compounds is not associated with circulating cells in most patients; however, substantial amounts of gold have been found in the erythrocytes of about one-third of patients receiving parenteral chrysotherapy for rheumatoid arthritis. The clinical importance of this has not been determined. Small amounts of gold are also associated with lymphocytes. Distribution of gold from gold sodium thiomalate into erythrocytes is increased in rheumatoid arthritis patients who smoke cigarettes.
In vivo, the extent to which gold from parenteral gold compounds is bound to plasma proteins is high (generally 85-95% or higher in most patients), but variable depending on the extent of association with circulating erythrocytes. Of the gold bound to plasma proteins, about 85-95% is bound to albumin.
Gold has been shown to cross the placenta in pregnant women receiving gold sodium thiomalate. Small amounts of gold have been shown to be distributed into milk in women receiving aurothioglucose or gold sodium thiomalate.
Elimination
The biologic half-life of gold following a single 50-mg dose of a parenteral gold compound has been reported to range from 3-27 days. Following successive weekly doses, the half-life increases and may be 14-40 days after the third dose and up to 168 days after 11 weekly injections. In one study following single 10-mg doses of gold sodium thiomalate, serum gold concentrations showed a biphasic decline with a relatively rapid early phase (serum half-life about 43 hours) and a slow late phase (serum half-life about 6 days). The slow phase of decline may result from excretion and the rapid phase of decline may result from tissue distribution. The true potential of gold compounds, including aurothioglucose and gold sodium thiomalate, to cumulate 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.
The metabolic fate of the parenteral gold compounds is obscure but it has been suggested that the drugs are not broken down to an elemental form of gold. Excretion of the parenteral gold compounds is slow. About 70% (range: 50-90%) of the gold from a dose of a parenteral gold compound is excreted in urine and about 30% (range: 10-50%) in feces. Fecal excretion is somewhat erratic but tends to be low on the first day after an injection and to increase over the next several days. When a total dose of 1 g of a parenteral gold compound has been administered, the urinary excretion of gold can be detected for as long as 12-15 months after the drug has been discontinued. Some studies indicate that during therapy with 50-mg weekly doses the total amount excreted during a week is about 40% from the most recent dose and about 60% from previous doses. Heavy metal antagonists containing sulfhydryl groups such as dimercaprol and penicillamine chelate gold and increase the excretion of gold from parenteral gold compounds.
Limited data indicate that gold from gold sodium thiomalate is partially removed by peritoneal dialysis.
Chemistry and Stability
Chemistry
Aurothioglucose and gold sodium thiomalate are parenterally administered gold compounds. Aurothioglucose and gold sodium thiomalate are organic coordination compounds in which gold(I) is complexed with thioglucose and thiomalate, respectively, via a sulfur atom. Like the gold in the orally active gold compound, auranofin, the gold in these parenteral gold compounds is attached to sulfur; however, unlike the gold in auranofin, the gold in each of these parenteral gold compounds is not attached to other specific groups, but rather is apparently attached to the sulfur of its other molecules, resulting in the existence of the drugs as polymers (or oligomers). In addition, unlike auranofin, these parenteral gold compounds are hydrophilic, have a net ionic charge in solution, and possibly react more strongly with sulfhydryl groups.
Aurothioglucose
Aurothioglucose occurs as a yellow powder that is odorless or has a slight mercaptan-like odor and contains approximately 50% gold. The drug is freely soluble in water, practically insoluble in alcohol, and insoluble in vegetable oils. Because aqueous solutions of aurothioglucose decompose on standing, the drug is used as a suspension in anhydrous vegetable oils. Commercially available aurothioglucose is a suspension in sesame oil, and also contains aluminum monostearate and propylparaben as a preservative.
Gold Sodium Thiomalate
Gold sodium thiomalate occurs as a white to yellowish-white, odorless or practically odorless, lumpy solid and contains approximately 50% gold. The drug is very soluble in water and insoluble in alcohol. The commercially available gold sodium thiomalate injection occurs as a light yellow to yellow solution and has a pH of 5.8-6.5 and contains benzyl alcohol as a preservative.
Stability
Sterile aurothioglucose suspension and gold sodium thiomalate injection should be protected from light and stored at a temperature less than 40°C, preferably at 15-30°C; freezing should be avoided. Gold sodium thiomalate injection should not be used if the color is darker than a pale yellow. Following the date of manufacture, sterile aurothioglucose suspension and gold sodium thiomalate injection have expiration dates of 5 years.