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GOLD DRUGS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Gold drugs are chiefly used in rheumatoid arthritis.
    B) Their use has markedly declined since the oral methotrexate protocol has come into common use and questions concerning the efficacy of gold have surfaced.

Specific Substances

    A) GOLD SODIUM THIOGLUCOSE
    1) 1-thio-D-glucopyranosate gold
    2) (D-glucosylthio) gold
    3) 1-aurothio-D-glucopyranose
    4) GTG
    5) Aurothioglucose
    6) Solganal(R)
    GOLD SODIUM THIOMALATE
    1) GST
    2) Sodium aurothiomalate
    3) Sodium aurothiosuccinate
    4) Myochrysine(R)
    GOLD THIOSULFATE
    1) Sodium aurothiosulfate
    2) Sanocrysin(R)
    GOLD THIOGLYCANIDE
    1) Aurothioglycanide
    2) Alpha-auromercaptoacetanile
    3) 2-aurothio-N-phenylacetamide
    AURANOFIN
    1) SKF D-39162
    2) 1-thio-beta-D-glycophyranosato-triethyl-phosphine gold
    3) 2, 3, 4, 6-tetra-acetate triethylphosphine gold
    GOLD THIOPOLYPEPTIDE
    1) GTPP
    GENERAL TERM
    1) Gold salts

Available Forms Sources

    A) FORMS
    1) GOLD SODIUM THIOGLUCOSE - This drug is for parenteral use and is available in 50 mg/mL vials.
    2) GOLD SODIUM THIOMALATE - This is an injectable gold salt containing approximately 50% gold. It comes in 10, 25, 50, and 100 mg/mL ampules.
    3) GOLD THIOSULFATE - This is used IV; injections are painful.
    4) GOLD THIOGLYCANIDe
    5) AURANOFIN - This is an oral salt containing approximately 29% gold. The drug is currently being sold in West Germany, Argentina, Italy, and the United States under the trade name Ridura(R). The dosage strength is 3 mg, equivalent to 0.9 mg of gold.
    6) GOLD THIOPOLYPEPTIDE - This compound is used primarily in Europe (Blocka et al, 1986).
    B) USES
    1) Gold drugs are chiefly used in rheumatoid arthritis (Short et al, 1946; Epstein et al, 1991).
    2) Their use has markedly declined since the oral methotrexate protocol has come into common use and questions concerning the efficacy of gold have surfaced (Fernandez-Herlihy, 1991; Felson et al, 1990).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Most data is derived from adverse effects reported at therapeutic doses. Use of gold in chronic treatment of rheumatoid arthritis has declined since the oral methotrexate protocol has come into common use, and questions of the efficacy of gold have surfaced.
    2) There is a high incidence of toxic reactions with gold when used for rheumatoid arthritis.
    a) Incidence is from 5 to 50%.
    b) The rate of serious reactions is approximately 3%.
    c) There seems to be no correlation between blood gold levels and toxicity or therapeutic effect.
    d) Common problems with therapeutic use include allergic dermatitis (12% to 55%), stomatitis, alopecia, hypersensitivity pneumonitis, drug-induced lupus, and rarely thrombocytopenia (incidence about 1%).
    B) WITH POISONING/EXPOSURE
    1) Overdose effects would be expected to be extensions of toxic therapeutic effects. Ventricular tachycardia was reported in one case. Until 1984, therapeutic gold drugs were only available parenterally.
    0.2.4) HEENT
    A) Stomatitis is the second most common reaction. Glossitis and gingivitis may also develop. Ocular inflammation, ocular ulcers, and keratitis have also been reported.
    B) Corneal deposits of metallic gold have been observed.
    0.2.5) CARDIOVASCULAR
    A) Ventricular tachycardia and vasomotor reactions have been reported.
    B) Myocardial infarction has been observed following a vasomotor reaction.
    0.2.6) RESPIRATORY
    A) Toxic pulmonary reactions to gold have been reported. They may be manifested by a diffuse interstitial pneumonitis and fibrosis.
    0.2.7) NEUROLOGIC
    A) Encephalopathy, neuropathy, stroke, myokymia, Guillain-Barre syndrome, and encephalomyelitis have all been reported.
    0.2.8) GASTROINTESTINAL
    A) Gastrointestinal side effects are fairly common. Symptoms range from diarrhea to severe colitis.
    0.2.9) HEPATIC
    A) Hepatitis and jaundice is a rare effect of therapeutic administration.
    B) Fulminant hepatic necrosis has occurred.
    0.2.10) GENITOURINARY
    A) Proteinuria, nephritis, and renal cortical degeneration have been reported.
    B) Vaginitis has been reported.
    0.2.13) HEMATOLOGIC
    A) Thrombocytopenia, aplastic anemia, agranulocytosis, eosinophilia, and neutropenia may occur.
    0.2.14) DERMATOLOGIC
    A) Dermatologic reactions to gold salts are the most common effects. The incidence of gold drugs causing dermatitis or pruritus ranges from 12% to 55%.
    0.2.16) ENDOCRINE
    A) Gynecomastia has been reported.
    0.2.20) REPRODUCTIVE
    A) Aurothioglucose and gold sodium thiomalate are in pregnancy category C. Gold has been detected in the liver and kidneys of an intentionally aborted fetus and in the placenta. Gold is excreted in breast milk, but in quantities not shown to be harmful.

Laboratory Monitoring

    A) "Normal" gold urine levels during therapy vary considerably. Serum concentrations after single 50 mg IM dose was 255 mcg/mL at 168 hours after injection. It is thought that auranofin 3 mg twice daily for 12 weeks would produce blood levels of 0.7 mcg/mL.
    B) Parameters to monitor are urinalysis (proteinuria and hematuria), complete blood counts (hematologic abnormalities), and liver function tests.
    C) ABGs and PFTs are indicated in patients with pulmonary symptoms.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Experience with activated charcoal in gold toxicities is limited.
    1) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) GOLD LUNG TOXICITY has been treated with administration of corticosteroids.
    C) HEMATOLOGIC REACTIONS - Are treated by splenectomy, chelation therapy, immunosuppressives, and steroids.
    D) CHELATION - Chelation has been used to reduce the amount of circulating gold, but its efficacy is unclear.
    1) BAL - Has been used to treat gold toxicity; the side effects associated with BAL limit its use. The dose administered varies by case. A common dose for BAL is 3 to 5 mg/kg/dose every 4 hours deep IM the first 2 days, then 2.5 to 3 mg/kg/dose IM every 6 hours for 2 days, then 2.5 to 3 mg/kg every 12 hrs for a week IM.
    2) D-PENICILLAMINE - This agent has been successfully used to treat skin reactions and thrombocytopenia in cases where BAL and corticosteroids showed initial but not sustained success.
    a) D-PENICILLAMINE: Use only if less toxic agents not available or not tolerated. USUAL DOSE: ADULT: 1 to 1.5 g/day given orally in 4 divided doses. CHILD: 15 to 30 mg/kg/day in 3 to 4 divided doses. Initially, a small dose may be given to minimize side effects and then increased gradually (eg, 25% of the desired dose in week 1, 50% in week 2, and the full dose by week 3). Avoid if penicillin allergic. Monitor for proteinuria, hematuria, rash, leukopenia, thrombocytopenia.
    3) N-ACETYLCYSTEINE/NAC - This agent has been used to remove/redistribute gold and reduce hematologic reactions. Dose: 2 to 9 g in 100 mL of D5W or 0.45 percent sodium chloride intravenously over 2 to 6 hours. Total dose per therapy for NAC ranged from 13 to 153 g.
    E) Cyclophosphamide is the most successful of the immunosuppressives used. The dose of cyclophosphamide is 100 mg every day times 6 months (until platelets stabilize at 100,000 per cubic mm) and then reduce to 75 mg/day.
    F) Granulocyte colony-stimulating factor has been used to treat gold-induced granulocytopenia. Usual subcutaneous starting dose is 5 micrograms/kilogram/day filgrastim .
    0.4.6) PARENTERAL EXPOSURE
    A) GOLD LUNG TOXICITY has been treated with administration of corticosteroids.
    B) HEMATOLOGIC REACTIONS - Are treated by splenectomy, chelation therapy, immunosuppressives, and steroids.
    1) BAL - Has been used to treat gold toxicity, but the side effects associated with BAL limit its use. The dose administered varies by case. A common dose for BAL is 3 to 5 mg/kg/dose every 4 hours deep IM the first 2 days, then 2.5 to 3 mg/kg/dose IM every 6 hours for 2 days, then 2.5 to 3 mg/kg IM every 12 hours for one week.
    2) D-PENICILLAMINE - This agent has been successfully used to treat skin reactions and thrombocytopenia in cases where BAL and corticosteroids showed initial but not sustained success.
    3) N-ACETYLCYSTEINE/NAC - This agent has been used to remove/redistribute gold and reduce hematologic reactions. Dose: 2 to 9 g in 100 mL of D5W or 0.45 percent sodium chloride intravenously over 2 to 6 hours. Total dose per therapy for NAC ranged from 13 to 153 g.
    4) IMMUNOSUPPRESSIVES - Cyclophosphamide is the most successful of the immunosuppressives used. The dose of cyclophosphamide is 100 mg every day times 6 months (until platelets stabilize at 100,000 per cubic mm) and then reduce to 75 mg/day.

Range Of Toxicity

    A) There appears to be little correlation between total gold dose and toxicity. In a summary of 20 cases of toxicity, the cumulative toxic dose was from 230 mg to 10 g of gold salt. Acute administration of intramuscular aurothioglucose 500 mg in one adult and 1000 mg in another did not cause acute toxicity.

Clinical Effects

Heent

    3.4.1) SUMMARY
    A) Stomatitis is the second most common reaction. Glossitis and gingivitis may also develop. Ocular inflammation, ocular ulcers, and keratitis have also been reported.
    B) Corneal deposits of metallic gold have been observed.
    3.4.3) EYES
    A) INFLAMMATION - Ocular inflammation has been reported.
    B) ULCERS - Ocular ulcers have been reported.
    C) KERATITIS may occur.
    D) GOLD DEPOSITS - Deposits of metallic gold in the corneas have been reported (Bron et al, 1979).
    E) REVERSIBILITY - Ocular effects of gold therapy are generally reversible (Rodenhauser & Behrend, 1969).
    3.4.6) THROAT
    A) STOMATITIS is the second most common adverse reaction of gold therapy (McCarty et al, 1962). The incidence of mouth ulcers during the first 3 months of therapy in one study was 4 per 10,000 patient-months (Kean & Anastassiades, 1979). Extensive cheilitis has been reported (Burrows et al, 1994).
    B) GLOSSITIS and gingivitis may develop. Shallow tongue ulcers have been reported following 3 months of weekly gold therapy (Burrows et al, 1994).

Cardiovascular

    3.5.1) SUMMARY
    A) Ventricular tachycardia and vasomotor reactions have been reported.
    B) Myocardial infarction has been observed following a vasomotor reaction.
    3.5.2) CLINICAL EFFECTS
    A) VENTRICULAR TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - A 32-year-old patient presented with dizziness, general weakness, and palpitation 3 hours after receiving 500 mg of myocrisin (sodium aurothiomalate) instead of 50 mg. An ECG showed ventricular tachycardia. She received lidocaine and converted to sinus rhythm with repetitive bouts of ventricular tachycardia. About 3 hours after the overdose she received BAL (3 mg/kg) and one hour later she was in sinus rhythm without further dysrhythmias (Scharf et al, 1976).
    B) VASODILATATION
    1) WITH THERAPEUTIC USE
    a) Vasomotor reactions, characterized by nausea, vomiting, facial flushing, dizziness, and fainting, may occur in patients treated with gold sodium thiomalate, presumably as a result of peripheral vasodilatation. These effects are also known as "nitritoid reactions", as they resemble the adverse effects caused by the nitrates used to treat angina pectoris. This effect seems to be peculiar to gold sodium thiomalate, and is usually not seen upon administration of aurothioglucose or auranofin. It typically occurs within minutes of injection (Cohen, 1988).
    b) CASE REPORT - A vasomotor reaction (nitritoid reaction) is reported following 20 months of oral auranofin, 6 mg/day, in a woman who had previously had nitritoid reactions to injectable gold sodium thiomalate. The attacks occurred 4 to 12 hours following her auranofin dose, and they occurred at unpredictable intervals, with spontaneous resolution within a few minutes (Proudman & Cleland, 1992).
    C) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) Myocardial infarction has been reported following a nitritoid reaction (Gottlieb & Brown, 1977).
    D) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Profound hypotension has been reported as part of the nitritoid reaction (Hill et al, 1995).

Respiratory

    3.6.1) SUMMARY
    A) Toxic pulmonary reactions to gold have been reported. They may be manifested by a diffuse interstitial pneumonitis and fibrosis.
    3.6.2) CLINICAL EFFECTS
    A) FIBROSIS OF LUNG
    1) WITH THERAPEUTIC USE
    a) Toxic pulmonary reactions to gold have been reported. They may be manifested by a diffuse interstitial pneumonitis and fibrosis. Pulmonary function testing may show restrictive lung disease, decreased diffusing capacity and oxygen desaturation with exercise (Blackwell & Gossage, 1995).
    b) Onset may be insidious, producing symptoms of dry cough, eosinophilia, rash, and malaise (Miyachi, 1976; Ward et al, 1983; Blackwell & Gossage, 1995). Pulmonary function may return to normal on discontinuation of the gold salt.
    B) INTERSTITIAL LUNG DISEASE
    1) WITH THERAPEUTIC USE
    a) CHRONIC TOXICITY
    1) In a meta-analysis of 140 cases of gold-induced pulmonary disease (median treatment 30 months (range 1 to 84 months)), dyspnea (92%) and cough (67%) were observed frequently (Tomioka & King, 1997). In addition, 80% had abnormal PFTs and bronchoalveolar lavage (BAL) lymphocytes were increased in 71.9% of patients. Most patients were treated with corticosteroids with complete remission of symptoms.
    a) No significant difference in demographic data, type of gold therapy, total dose, or duration of treatment were found between those patients who developed gold-induced interstitial lung disease and a chart review of cases (n=208) with rheumatoid interstitial lung disease.

Neurologic

    3.7.1) SUMMARY
    A) Encephalopathy, neuropathy, stroke, myokymia, Guillain-Barre syndrome, and encephalomyelitis have all been reported.
    3.7.2) CLINICAL EFFECTS
    A) TOXIC ENCEPHALOPATHY
    1) Encephalopathy has been reported following therapeutic doses (McAuley et al, 1977); one case responded promptly to chelation therapy with dimercaprol (Perry & Jacobsen, 1984).
    B) CEREBROVASCULAR DISEASE
    1) WITH THERAPEUTIC USE
    a) A stroke-like syndrome has been reported following a nitritoid reaction associated with hypotension after intramuscular injections of gold sodium thiomalate (Prupas, 1984; Hill et al, 1995).
    b) CASE REPORT - One patient developed a cerebrovascular accident following a nitritoid reaction associated with profound hypotension, with residual deficits of left hemiplegia, left hemianesthesia, and left visual inattention (Hill et al, 1995).
    C) SPASMODIC MOVEMENT
    1) WITH THERAPEUTIC USE
    a) Myokymia has been reported following therapeutic use of gold sodium thiomalate (Griswold & Mamoli, 1984; Caldron et al, 1987).
    D) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) A Guillain-Barre type polyneuropathy has been associated with sodium aurothiomalate (Dick & Raman, 1982; Schlumpf et al, 1983).
    b) Nitritoid reactions to gold salts resulted in pain, paresthesias, and altered pin-prick sensations in a T10 to T12 dermatomal distribution which was felt to be secondary to spinal cord ischemia in one patient (Hill et al, 1995).
    c) CASE REPORT - A 50-year-old man with rheumatoid arthritis developed peripheral neuropathy after receiving gold salts (a total dose of 545 mg). Neurologic examination showed areflexia and weakness of extremities. A lumbar puncture showed elevated protein. A muscle biopsy showed focal atrophy, myxomatous degeneration of nerve fibers and no arteritis. Following the discontinuation of gold and tapering doses of prednisone, he recovered completely after 6 weeks. Nine years later, once again he developed peripheral neuropathy after receiving gold (a total dose of 500 mg). Examination showed areflexia and weakness of extremities with decreased vibratory sense and light touch. Nerve conduction revealed decreased slowing and amplitudes. Following the discontinuation of gold, his symptoms resolved completely after 8 weeks (Gerkin, 2001).
    d) CASE REPORT - A 63-year-old man diagnosed 4 months earlier with RA, presented with weight loss, weakness, and fever 2.5 weeks after initiating gold therapy (150 mg total gold dose). Laboratory studies revealed elevated liver enzymes (AST 372 Units/L, ALT 903 Units/L) and bilirubin (7.1 mg/dL, which peaked at 25.8 mg/dL). The patient also had elevated WBC (3700 cells/mm(3)) and amylase (967 Units/L) consistent with pancreatitis, and developed polyneuropathy 2 weeks after admission. Gold therapy was discontinued, and a positive lymphocyte transformation test (LTT) indicated a cell mediated hypersensitivity to gold. All laboratory values returned to normal within 4 months, and complete resolution of neural symptoms was seen at 1 year follow-up (Ben-Ami et al, 1999)I.
    E) ENCEPHALITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A case of acute disseminated encephalomyelitis due to gold therapy was reported by Cohen et al (1985). The patient experienced symptoms approximately six hours after each dose, which persisted until the following day. One week after the last injection, she woke with severe neurological symptoms. She was treated with oral prednisolone, and at 18 weeks she still showed residual neurologic deficit despite substantial improvement (Cohen et al, 1985).

Gastrointestinal

    3.8.1) SUMMARY
    A) Gastrointestinal side effects are fairly common. Symptoms range from diarrhea to severe colitis.
    3.8.2) CLINICAL EFFECTS
    A) COLITIS
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal side effects are fairly common. Symptoms may range from mild, reversible diarrhea (Ward et al, 1983) to severe colitis (Dorta et al, 1993; Nisar & Winfield, 1994).
    b) CASE REPORT - Nisar & Winfield (1994) reported a case of severe enterocolitis occurring after the third weekly injection of sodium aurothiomalate. Surgery revealed an intraluminal fecal impaction, pericolitis, and peritonitis and macroscopic impression suggestive of an imminent perforation of the sigmoid colon (Nisar & Winfield, 1994).
    B) GASTROENTERITIS
    1) WITH THERAPEUTIC USE
    a) Panenteritis may occur (Ward et al, 1983; Roe et al, 1972).
    C) ACUTE PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 63-year-old man diagnosed 4 months earlier with RA, presented with weight loss, weakness, and fever 2.5 weeks after initiating gold therapy (150 mg total gold dose). Laboratory studies revealed elevated amylase (967 Units/L) consistent with pancreatitis. The patient also had elevated liver enzymes (AST 372 Units/L, ALT 903 Units/L) and bilirubin (7.1 mg/dL, which peaked at 25.8 mg/dL), and developed polyneuropathy 2 weeks after admission. Gold therapy was discontinued, and a positive lymphocyte transformation test (LTT) indicated a cell mediated hypersensitivity to gold. All laboratory values returned to normal within 4 months, and complete resolution of neurologic symptoms was seen at 1 year follow-up (Ben-Ami et al, 1999).

Hepatic

    3.9.1) SUMMARY
    A) Hepatitis and jaundice is a rare effect of therapeutic administration.
    B) Fulminant hepatic necrosis has occurred.
    3.9.2) CLINICAL EFFECTS
    A) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Cholestatic jaundice has occurred following therapeutic administration (McCarty et al, 1962; Kean & Anastassiades, 1979). In one case, cholestatic jaundice occurred after only 3 weekly doses of 50 mg and one 10 mg test dose of injectable gold (sodium aurothiomalate) (Nisar & Winfield, 1994). Discontinuation of the gold therapy will usually result in gradual resolution of the cholestasis.
    b) CASE REPORT - Cholestatic hepatitis was reported in an adult 3 weeks after administration of aurothioglucose (total cumulative dose 160 mg). Four weeks after discontinuing therapy, liver function returned to normal. The authors suggested that the mechanism may be due to an idiosyncratic response or direct toxicity due to gold accumulation in the lysosomes of the hepatic macrophages (te Boekhorst et al, 1999).
    c) CASE REPORT - A 63-year-old man diagnosed 4 months earlier with RA, presented with weight loss, weakness, and fever 2.5 weeks after initiating gold therapy (150 mg total gold dose). Laboratory studies revealed elevated liver enzymes (AST 372 Units/L, ALT 903 Units/L) and bilirubin (7.1 mg/dL, which peaked at 25.8 mg/dL). The patient also had elevated amylase (967 Units/L) consistent with pancreatitis, and developed polyneuropathy 2 weeks after admission. Gold therapy was discontinued, and a positive lymphocyte transformation test (LTT) indicated a cell mediated hypersensitivity to gold. All laboratory values returned to normal within 4 months, and complete resolution of neural symptoms was seen at 1 year follow-up (Ben-Ami et al, 1999)I.
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT - A 49-year-old woman with rheumatoid arthritis presented with vomiting, asthenia, fever, jaundice, and disseminated pruriginous erythematosquamous papular lesions 3 weeks after receiving intramuscular injections of sodium aurothiopropanolsulfonate (a cumulative dose of 600 mg [400 mg of this dose administered in less than a week]). Laboratory results showed elevated liver enzymes. Liver biopsy showed cholestatic hepatitis with cholangitis evolving towards prolonged cholestasis with ductopenia. Sialadenitis with sicca syndrome was also observed 6 months after onset of the disease. The authors suggested that the mechanism may be immunoallergic since liver lesions were associated with hypersensitivity syndrome including dermatitis and blood and tissue eosinophilia (Basset et al, 2003).
    B) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Hepatitis has been reported with therapeutic administration (McCarty et al, 1962; Kean & Anastassiades, 1979).
    C) HEPATIC NECROSIS
    1) CASE REPORT - Two patients with seronegative rheumatoid arthritis developed fulminant, fatal hepatic necrosis following the institution of parenteral gold therapy. Both patients were also taking nonsteroidal anti-inflammatory drugs; this may also have contributed to the severe hepatocellular injury (Watkins et al, 1988).
    2) CASE REPORT - A patient with pemphigus vulgaris receiving weekly injectable gold sodium thiomalate in addition to dexamethasone developed acute hepatitis following a total cumulative dose of 85 mg of gold therapy. Hepatonecrosis was diagnosed, and the gold therapy was discontinued. Serum hepatic enzyme levels gradually returned to normal, and the patient was continued on monotherapy of dexamethasone (Rye & Krusinski, 1993).

Genitourinary

    3.10.1) SUMMARY
    A) Proteinuria, nephritis, and renal cortical degeneration have been reported.
    B) Vaginitis has been reported.
    3.10.2) CLINICAL EFFECTS
    A) ALBUMINURIA
    1) WITH THERAPEUTIC USE
    a) Proteinuria may occur (Kozloff et al, 1979). The incidence of this adverse effect during the first 3 months of therapy was reported as 1.8 episodes per 10,000 patient-months (Kean & Anastassiades, 1979).
    B) TOXIC NEPHROPATHY
    1) WITH THERAPEUTIC USE
    a) Nephropathy, manifesting as proteinuria, is a fairly common adverse effect of sodium aurothiomalate treatment. Nephritis and renal cortical degeneration have been reported (McCarty et al, 1962). Membranous nephritis (with dense deposits of IgG, IgM, and beta 1C) was reported in one case. It was suggested that there was an immune complex method of toxicity (Katz & Little, 1973).
    b) CASE SERIES - In a study of patients with rheumatoid arthritis who received treatment with gold drugs, Sakkas et al (1993) found a higher incidence (59% vs 14%) of HLA-DQA region genes in those who developed gold induced nephropathy as compared to those who did not (Sakkas et al, 1993).
    C) VAGINITIS
    1) WITH THERAPEUTIC USE
    a) Vaginitis has been reported (Webster & Juden, 1978).
    D) BLOOD IN URINE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - A 59-year-old woman developed elevated liver enzymes 3 weeks after receiving 500 mg of aurothioglucose intramuscularly instead of the usual dose of 50 mg. Urinalysis showed microhematuria and granular casts without proteinuria. Liver enzyme levels resolved spontaneously within 4 weeks (Pik et al, 1985).

Hematologic

    3.13.1) SUMMARY
    A) Thrombocytopenia, aplastic anemia, agranulocytosis, eosinophilia, and neutropenia may occur.
    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) CHRONIC TOXICITY
    1) Thrombocytopenia is a serious complication of gold therapy (Kozloff et al, 1979). It may occur during or several months after gold therapy is discontinued (Hazlett & Yendt, 1958). One to 3% of rheumatoid arthritis patients on gold therapy will develop myelotoxicity necessitating withdrawal of the drug. The majority of cases, however, develop mild thrombocytopenia (platelets 100 to 150 x 10(9)/L) which are reversible (Cervi et al, 1992).
    2) CASE SERIES - In a study of 55 cases, the majority slowly developed blood cell abnormalities, and blood tests would probably have been useful to diagnose the problems early. A small percentage, however, developed the abnormalities with little or no warning (Kay, 1973).
    3) CASE SERIES - In a review of cases sent to the Danish reporting system on adverse drug reactions, 309 cases of thrombocytopenia by noncytotoxic drugs were identified during 1968-1991; gold salts caused 10.6% (n=35) of cases reported (Pedersen-Bjergaard et al, 1996).
    B) APLASTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Aplastic anemia is a rare complication of gold therapy, and may be a serious, less reversible, and life threatening event. Aplastic anemia and agranulocytosis have both been reported (McCarty et al, 1962; Cervi et al, 1992).
    b) CASE REPORT - McGirr et al (1985) reported a case of aplastic anemia due to sodium aurothiomalate in a 56-year-old woman, which responded to antithymocyte globulin (McGirr et al, 1985).
    c) Red cell aplasia has been reported in several cases (Reid & Patterson, 1977).
    d) CASE REPORT - A progressive pure red cell aplasia with concomitant hepatotoxicity has been reported in a 54-year-old man after a total dose of 160 mg of gold (sodium thiomalate) was administered. Treatment consisting of prednisone and N-acetylcysteine infusions was associated with complete hematologic recovery (Hansen et al, 1991).
    C) EOSINOPHIL COUNT RAISED
    1) WITH THERAPEUTIC USE
    a) Eosinophilia is another toxic hematologic reaction to gold. In some studies, as high as 40% of the patients on gold therapy develop this toxic reaction. Eosinophilia and elevated IgE levels have been highly correlated (Davis & Hughes, 1974).
    D) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia may occur (Swanson & Cook, 1980; Thompson et al, 1978).
    b) CASE REPORT - Collins et al (1993) reported a case of a 65-year-old woman with an absolute neutropenia following a total of 460 mg sodium aurothiomalate injections. Bone marrow examination showed almost absent granulopoiesis and reduced erythropoiesis with normal megakaryocytes. Therapy with granulocyte colony-stimulating factor (G-CSF) was successful in reversing the neutropenia (Collins et al, 1993).
    E) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Bone marrow depression may occur (McCarty et al, 1962).

Dermatologic

    3.14.1) SUMMARY
    A) Dermatologic reactions to gold salts are the most common effects. The incidence of gold drugs causing dermatitis or pruritus ranges from 12% to 55%.
    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Dermatologic reactions to gold salts are the most common toxic effects, and may include eruptions resembling lichen planus, seborrheic dermatitis, pityriasis rosea, erythema nodosum, and pruritus (McCarty et al, 1962; Tsuji et al, 1992; Brown et al, 1993; Thompson & Skaehill, 1994). The incidence of gold drugs causing dermatitis ranges from 12% to 55% and has in some cases been associated with the vehicle used for injection (Lawrence, 1976).
    1) In a study done by Davis & Hughes (1974), skin reactions were highly correlated with the occurrence of eosinophilia. The incidence of rashes during the first 3 months was reported as 9.8 per 10,000 patient-months (Kean & Anastassiades, 1979). Erythema nodosa is a common reaction reported by physicians using gold drugs (Pennys et al, 1976).
    2) CASE REPORT - Erythema annulare centrifugum-like eruption was reported in 2 women, following 6 months and 6 years of therapy, respectively, with gold thiomalate. A lymphocyte stimulation test was positive in one and negative in the other (Tsuji et al, 1992).
    b) CASE SERIES - Svensson & Theander (1992) showed, through a prospective study of 45 patients, there was no significant increase in mucocutaneous adverse effects in rheumatoid patients with pre-existing mucocutaneous reactions who were administered injectable gold drugs. Therefore, a pre-existing dermatitis is not an absolute contraindication to the administration of gold drugs (Svensson & Theander, 1992).
    c) Rheumatoid patients with an HLA-DR1 (and/or -DR4) positive gene may be more susceptible to the mucocutaneous adverse effects of gold therapy (Pickl et al, 1993).
    d) CASE REPORT - A 49-year-old woman with rheumatoid arthritis presented with vomiting, asthenia, fever, jaundice, elevated liver enzymes, and disseminated pruriginous erythematosquamous papular lesions 3 weeks after receiving intramuscular injections of sodium aurothiopropanolsulfonate (a cumulative dose of 600 mg [400 mg of this dose administered in less than a week]). Skin biopsy findings (keratinocyte necrosis, dermal perivascular mononuclear infiltrate with occasional eosinophils) suggested drug-induced lesions. The authors suggested that the mechanism may be immunoallergic since liver lesions were associated with hypersensitivity syndrome including dermatitis and blood and tissue eosinophilia (Basset et al, 2003).
    B) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Diffuse hair loss with areas of scarring alopecia and follicular hyperkeratosis was reported in a 73-year-old woman following 3 months of weekly gold injections (Burrows et al, 1994).
    C) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Gold salts have been implicated as causative agents of Stevens-Johnson syndrome (Araujo & Flowers, 1984).
    D) DISORDER OF NAIL
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 34-year-old woman with severe rheumatoid arthritis developed yellow thickening of all 20 nails after receiving gold salts (total cumulative dose 90 mg/kg) over a 4 year period. Examination revealed gold discoloration of all the toenails and the distal two-thirds of all the fingernails, with loss of the lunulae. Thickening of the nail plate, increased transverse curvature, and mild subungual hyperkeratosis were also observed. In addition, both thumbnails and the right little fingernail were onycholytic (the left thumbnail was eventually shed). Following the discontinuation of gold salt therapy, the yellow discoloration gradually improved over the next 6 months. At this time, on both thumbnails where the change in growth rate occurred, a transverse depression of the nail plate (beau's line) was noted (Roest & Ratnavel, 2001).

Endocrine

    3.16.1) SUMMARY
    A) Gynecomastia has been reported.
    3.16.2) CLINICAL EFFECTS
    A) GYNECOMASTIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Gynecomastia was described in a 41-year-old man after receiving auranofin intermittently over a seven-month period (Williams, 1988). However, in the absence of rechallenge, it is unclear whether auranofin was the actual cause of the patient's gynecomastia.

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Immediate hypersensitivity reactions characterized by fever, sweating, headache, and tachycardia have been reported (Kean & Anastassiades, 1979).
    b) Up to 30% of patients treated with gold drugs will develop adverse immune reactions, with in vivo or in vitro testing rarely demonstrating sensitization (Goldermann et al, 1993).
    c) Sabroe et al (1996) have demonstrated a 13% rate of contact allergy to gold sodium thiosulfate as shown on positive allergy patch testing (Sabroe et al, 1996).
    B) DISORDER OF IMMUNE FUNCTION
    1) WITH THERAPEUTIC USE
    a) GENETIC PREDISPOSITION - The immunogenetic background of rheumatoid arthritis patients has been shown to have an effect on the development of gold induced adverse effects. Rheumatoid arthritis patients with HLA-DQA region genes have been shown to be more susceptible to the development of gold induced nephropathy (Sakkas et al, 1993) while patients with HLA-DR1 (and/or -DR4) positive genes may be predisposed to developing mucocutaneous adverse effects of gold therapy (Pickl et al, 1993).

Reproductive

    3.20.1) SUMMARY
    A) Aurothioglucose and gold sodium thiomalate are in pregnancy category C. Gold has been detected in the liver and kidneys of an intentionally aborted fetus and in the placenta. Gold is excreted in breast milk, but in quantities not shown to be harmful.
    3.20.3) EFFECTS IN PREGNANCY
    A) PLACENTAL BARRIER
    1) Gold has been detected in the liver and kidneys of an intentionally aborted fetus and in the placenta (JEF Reynolds , 1976).
    B) PREGNANCY CATEGORY
    AUROTHIOGLUCOSEC
    GOLD SODIUM THIOMALATEC
    Reference: Briggs et al, 1998
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Gold is excreted in breast milk, but in quantities not shown to be harmful (White & White, 1980; Briggs et al, 1998).

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Most data is derived from adverse effects reported at therapeutic doses. Use of gold in chronic treatment of rheumatoid arthritis has declined since the oral methotrexate protocol has come into common use, and questions of the efficacy of gold have surfaced.
    2) There is a high incidence of toxic reactions with gold when used for rheumatoid arthritis.
    a) Incidence is from 5 to 50%.
    b) The rate of serious reactions is approximately 3%.
    c) There seems to be no correlation between blood gold levels and toxicity or therapeutic effect.
    d) Common problems with therapeutic use include allergic dermatitis (12% to 55%), stomatitis, alopecia, hypersensitivity pneumonitis, drug-induced lupus, and rarely thrombocytopenia (incidence about 1%).
    B) WITH POISONING/EXPOSURE
    1) Overdose effects would be expected to be extensions of toxic therapeutic effects. Ventricular tachycardia was reported in one case. Until 1984, therapeutic gold drugs were only available parenterally.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) "Normal" gold urine levels during therapy vary considerably. Serum concentrations after single 50 mg IM dose was 255 mcg/mL at 168 hours after injection. It is thought that auranofin 3 mg twice daily for 12 weeks would produce blood levels of 0.7 mcg/mL.
    B) Parameters to monitor are urinalysis (proteinuria and hematuria), complete blood counts (hematologic abnormalities), and liver function tests.
    C) ABGs and PFTs are indicated in patients with pulmonary symptoms.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Obtain complete blood counts to check for hematologic abnormalities.
    B) BLOOD/SERUM CHEMISTRY
    1) Monitor liver function tests.
    2) Serum gold levels are not very useful, since they do not correlate with therapeutic levels or toxic effects.
    3) NORMAL BLOOD LEVELS - "Normal" gold urinary levels during therapy vary considerably by the dose administered. For example, a patient who had received a total dose of 650 mg over time had an excretion level of 671 mcg/100 mL and in a similar case (130 mg total dose) a patient had a level of 247 mcg/100 mL 19 years later.
    a) Serum concentrations after a single 50 mg IM dose was 255 mcg/mL 168 hours after injection (Lorber et al, 1970).
    b) It is thought that 3 mg twice daily for 12 weeks would produce blood levels of 0.7 mcg/mL of auranofin (Bergloff et al, 1980).
    4.1.3) URINE
    A) URINALYSIS
    1) Obtain urinalysis to check for proteinuria/hematuria before each injection.
    4.1.4) OTHER
    A) OTHER
    1) PULMONARY FUNCTION TESTS
    a) Monitor pulmonary function tests and blood gases in patients with pulmonary symptoms. In chronic disease, decreases in VC and DLCO are most common (Tomioka & King, 1997).
    2) OTHER
    a) Bronchoalveolar lavage (BAL) may be useful in the diagnosis of gold-induced pulmonary disease. Lymphocytosis and a low CD4/CD8 cratio (less than 1) are common findings in BAL fluid (Tomioka & King, 1997).
    b) In cases of severe and persistent diarrhea it may be advisable to perform endoscopy.

Radiographic Studies

    A) CT
    1) In cases of gold-induced pulmonary disease, chest CT may show alveolar opacities along the bronchovascular bundles (Tomioka & King, 1997).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) "Normal" gold urine levels during therapy vary considerably. Serum concentrations after single 50 mg IM dose was 255 mcg/mL at 168 hours after injection. It is thought that auranofin 3 mg twice daily for 12 weeks would produce blood levels of 0.7 mcg/mL.
    B) Parameters to monitor are urinalysis (proteinuria and hematuria), complete blood counts (hematologic abnormalities), and liver function tests.
    C) ABGs and PFTs are indicated in patients with pulmonary symptoms.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) Metallic gold is poorly adsorbed by activated charcoal. Oral gold drugs have been available since 1984, experience with activated charcoal is limited.
    2) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) Metallic gold is poorly adsorbed by activated charcoal. Experience with activated charcoal is limited.
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) If a toxic reaction occurs during therapeutic administration, discontinue the use of the drug. Often, toxicity is reversible on discontinuation alone. The primary treatment for gold toxicity has been patient support during any hematologic, respiratory, and/or gastrointestinal reactions. Chelation has been used to reduce the amount of circulating gold, but its efficacy is unclear. It is nearly impossible to remove all the gold from the body.
    B) CORTICOSTEROID
    1) GOLD LUNG TOXICITY has been treated by administration of corticosteroids (the type and dose used have varied in each case). Recovery was gradual over 1 to 17 months. Some fibrotic changes may be irreversible (Geddes & Brostoff, 1976).
    C) MYELOSUPPRESSION
    1) HEMATOLOGIC REACTIONS have been treated by discontinuation of drug, splenectomy, and chelation (Kozloff et al, 1979; Godfrey et al, 1982):
    2) DIMERCAPROL/BAL
    a) CONTRAINDICATIONS: Do not use in patients with a history of allergy to peanuts or peanut products.
    b) DOSE: 3 to 5 milligrams/kilogram by deep intramuscular injection every 4 hours initially, decrease to every 6 to 12 hours after 2 days.
    c) ADVERSE EFFECTS: Are common and include hypertension, pain at the injection site, fever, urticaria and headaches. Treat with antihistamines, antihypertensives or cessation of drug.
    3) PENICILLAMINE
    a) Penicillamine was successful in treating THROMBOCYTOPENIA in a case where BAL and corticosteroids showed initial but not sustained success. The platelet counts were raised from the 2500 to 37,500 range to 57,500 to 185,000 (Bluhm et al, 1962).
    b) DOSE
    1) USUAL ADULT DOSE
    a) 1 to 1.5 g/day given orally in 4 divided doses (Nelson, 2011).
    2) USUAL PEDIATRIC DOSE
    a) 15 to 30 mg/kg/day in 3 to 4 divided doses. Initially, a small dose may be given to minimize side effects and then increased gradually (eg, 25% of the desired dose in week 1, 50% in week 2, and the full dose by week 3) (Caravati, 2004; Prod Info DEPEN(R) titratable oral tablets, 2009).
    3) Patients allergic to penicillin products may have cross-sensitivity to penicillamine (Prod Info DEPEN(R) titratable oral tablets, 2009).
    4) Monitor for proteinuria and hematuria; heavy metals may also cause renal toxicity (Prod Info DEPEN(R) titratable oral tablets, 2009).
    5) Monitor CBC with differential, platelet count, and hepatic enzymes (Prod Info DEPEN(R) titratable oral tablets, 2009).
    c) ADVERSE EFFECTS
    1) COMMON SIDE EFFECTS/CHRONIC DOSING: Fever, anorexia, nausea, vomiting, diarrhea, abdominal pain, proteinuria, and myalgia(Prod Info DEPEN(R) titratable oral tablets, 2009).
    a) SERIOUS ADVERSE EFFECTS: Nephrotic syndrome, hypersensitivity reactions, leukopenia, thrombocytopenia, aplastic anemia, agranulocytosis, cholestatic hepatitis, and various autoimmune responses (Prod Info DEPEN(R) titratable oral tablets, 2009; Feehally et al, 1987; Kay, 1986).
    d) PREGNANCY
    1) Penicillamine is considered FDA pregnancy category D(Prod Info CUPRIMINE(R) oral capsules, 2004); it should be avoided if possible in pregnant patients.
    2) Use of penicillamine throughout pregnancy has been associated with connective tissue abnormalities, hydrocephalus, cerebral palsy, cardiac and great vessel anomalies, webbing of fingers and toes, and arthrogryposis multipex (Linares et al, 1979; Solomon et al, 1977; Anon, 1981; Beck et al, 1981; Rosa, 1986). However, the teratogenic effect when used in low doses or for short periods of time, as in metal chelation, has yet to be determined.
    4) N-ACETYLCYSTEINE
    a) Hansen et al (1991) reported an adult case of progressive bone marrow depression treated with oral prednisone and acetylcysteine (NAC) 4 grams/day as a 6 hour infusion, and increased by 2 grams/day until a total dose of 10 grams/day was achieved (Hansen et al, 1991). This was given for 20 days prior to gradual withdrawal.
    5) CYCLOPHOSPHAMIDE -
    a) Cyclophosphamide is the most successful of the immunosuppressives used. The dose of cyclophosphamide is 100 mg every day times 6 months (until platelets stabilize at 100,000 per cubic mm) and then reduce to 75 mg/day (Kozloff et al, 1979).
    6) CORTICOSTEROIDS
    a) Hansen et al (1991) reported an adult case of progressive bone marrow depression treated with NAC and oral prednisone 1 milligram/kilogram/day for 20 days, with tapering therapy thereafter (Hansen et al, 1991).
    7) GRANULOCYTE COLONY-STIMULATING FACTOR (G-CSF) -
    a) G-CSF has been used to reverse gold-induced absolute neutropenia(Collins et al, 1993).
    1) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    D) DIARRHEA
    1) Colitis and severe diarrhea associated with oral auranofin has been ameliorated with oral cromolyn sodium suspension 20 milligrams four times a day (Michet et al, 1987).
    2) Dorta et al (1993) reported the use of subcutaneous octreotide 0.05 milligrams 3 times daily for one day, then 0.1 milligram twice daily for 12 weeks in an adult with gold-induced enteritis with associated persistent watery diarrhea (Dorta et al, 1993).
    E) CHELATION THERAPY
    1) Chelation has been used to reduce the amount of circulating gold, but its efficacy is unclear.
    2) DIMERCAPROL/BAL
    a) BAL has been used to treat gold toxicity; however the side effects associated with BAL limit its use.
    b) In a patient given 500 milligrams of Solganol(R), BAL therapy was instituted immediately. Clearance was 0.45 milliliter/minute for the first 4 to 6 days, 0.27 milliliter/minute on day 7 and 0.18 milliliter/minute on day 8. The normal excretion is estimated at 0.1 to 0.2 milliliter/minute (Bunch, 1974).
    c) The use of BAL is limited by its toxicity and occasionally by the short duration of its effects. The dose administered varies by case.
    d) A COMMON DOSE for BAL is 3 to 5 milligrams/kilogram/dose every 4 hours deep intramuscularly the first 2 days, 2.5 to 3 milligrams/kilogram/dose intramuscularly every 6 hours for 2 days, then 2.5 to 3 milligrams/kilogram every 12 hours for a week intramuscularly.
    e) Adverse reactions such as urticaria may respond to diphenhydramine. Hyperpyrexia and hypertension may also occur.
    F) PENICILLAMINE
    1) EFFICACY
    a) Laboratory experiments show penicillamine has a great affinity for ionic gold (dissociation constants K1 x K2 = 24.8), and complexes by way of both a nitrogen and a sulfur linkage. When tested in 9 patients, penicillamine enhanced the urinary excretion of gold (p less than 0.001) (Eyring & Engleman, 1963).
    b) This agent has been successfully used to treat SKIN REACTIONS. Doses of 250 milligrams orally 4 times a day for 11 days were used (Davis, 1969).
    c) Penicillamine was successful in treating THROMBOCYTOPENIA in a case where BAL and corticosteroids showed initial but not sustained success. The platelet counts were raised from the 2500 to 37,500 range to 57,500 to 185,000 (Bluhm et al, 1962).
    2) USUAL ADULT DOSE
    a) 1 to 1.5 g/day given orally in 4 divided doses (Nelson, 2011).
    3) USUAL PEDIATRIC DOSE
    a) 15 to 30 mg/kg/day in 3 to 4 divided doses. Initially, a small dose may be given to minimize side effects and then increased gradually (eg, 25% of the desired dose in week 1, 50% in week 2, and the full dose by week 3) (Caravati, 2004; Prod Info DEPEN(R) titratable oral tablets, 2009).
    4) PRECAUTIONS
    a) Patients allergic to penicillin products may have cross-sensitivity to penicillamine (Prod Info DEPEN(R) titratable oral tablets, 2009).
    b) Monitor for proteinuria and hematuria; heavy metals may also cause renal toxicity (Prod Info DEPEN(R) titratable oral tablets, 2009).
    c) Monitor CBC with differential, platelet count, and hepatic enzymes (Prod Info DEPEN(R) titratable oral tablets, 2009).
    5) ADVERSE EFFECTS
    a) COMMON SIDE EFFECTS/CHRONIC DOSING: Fever, anorexia, nausea, vomiting, diarrhea, abdominal pain, proteinuria, and myalgia(Prod Info DEPEN(R) titratable oral tablets, 2009).
    1) SERIOUS ADVERSE EFFECTS: Nephrotic syndrome, hypersensitivity reactions, leukopenia, thrombocytopenia, aplastic anemia, agranulocytosis, cholestatic hepatitis, and various autoimmune responses (Prod Info DEPEN(R) titratable oral tablets, 2009; Feehally et al, 1987; Kay, 1986).
    6) PREGNANCY
    a) Penicillamine is considered FDA pregnancy category D(Prod Info CUPRIMINE(R) oral capsules, 2004); it should be avoided if possible in pregnant patients.
    b) Use of penicillamine throughout pregnancy has been associated with connective tissue abnormalities, hydrocephalus, cerebral palsy, cardiac and great vessel anomalies, webbing of fingers and toes, and arthrogryposis multipex (Linares et al, 1979; Solomon et al, 1977; Anon, 1981; Beck et al, 1981; Rosa, 1986). However, the teratogenic effect when used in low doses or for short periods of time, as in metal chelation, has yet to be determined.
    G) ACETYLCYSTEINE
    1) This agent has been used to remove/redistribute gold and reduce hematologic reactions. There is a better chance of patient recovery if N-acetylcysteine (NAC) is given within 20 days of the last gold injection.
    2) Lorber et al (1973) demonstrated both in vitro and in vivo that NAC chelates gold.(Lorber et al, 1973a) As much as a 54% increase over normal excretion was observed in test subjects.
    a) They also used 3 to 6 grams/day intravenously for 7 days on 2 patients with thrombocytopenia and depressed granulocytic white cell counts. Both showed improvement in the numbers of cells within 3 days, and were normal in 2 weeks.
    3) Godfrey et al (1982) successfully treated several types of HEMATOLOGIC REACTIONS by using intravenous NAC in doses of 2 to 9 grams in 100 milliliters of D5W or 0.45 percent sodium chloride over 2 to 6 hours (Godfrey et al, 1982). The total dose per therapy for NAC ranged from 13 to 153 grams.
    H) CYCLOPHOSPHAMIDE
    1) Cyclophosphamide is the most successful of the immunosuppressives used. This drug was used to treat thrombocytopenia unresponsive to steroids and minimally responsive to BAL (2.5 milligrams/kilogram intramuscularly every 4 hours x 6 days then every 6 hours x 8 doses then once a day).
    2) The DOSE OF CYCLOPHOSPHAMIDE was 100 milligrams every day x 6 months (until platelets stabilized at 100,000 per cubic millimeter) and then reduced to 75 milligrams/day (Kozloff et al, 1979).
    3) Cyclophosphamide might be indicated in gold induced thrombocytopenia refractory to chelation therapy and where significant hemorrhagic risk is present (Kozloff et al, 1979).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Because of tissue binding and tissue sequestration, gold should not be significantly dialyzable.
    B) PERITONEAL DIALYSIS
    1) Garland et al (1988) reported a 13-year-old boy with severe juvenile rheumatoid arthritis who received gold sodium thiomalate 285 milligrams over a three-week period .
    2) Oliguria precluded d-penicillamine therapy, and peritoneal dialysis was instituted.
    3) The patient's peritoneal clearance of gold was approximately 0.5 milliliter/minute, and the authors concluded that peritoneal dialysis is of little value in removing gold from patients with gold toxicity and renal failure.

Abstracts

Case Reports

    A) ADULT
    1) SPECIFIC AGENT
    a) AURANOFIN
    1) Auranofin overdose (27 mg/day for 10 days) has resulted in peripheral neuropathy and encephalopathy, which resolved upon drug withdrawal (Prod Info Ridaura(R), auranofin, 1985).
    b) AUROTHIOGLUCOSE
    1) Pik et al (1985) reported two acute overdose cases in which patients received 1000 mg and 500 mg of intramuscular aurothioglucose, respectively. Both patients were asymptomatic and recovered uneventfully without treatment. One patient, however, developed microhematuria and granular casts without proteinuria which resolved spontaneously within four weeks (Pik et al, 1985).

Range Of Toxicity

Summary

    A) There appears to be little correlation between total gold dose and toxicity. In a summary of 20 cases of toxicity, the cumulative toxic dose was from 230 mg to 10 g of gold salt. Acute administration of intramuscular aurothioglucose 500 mg in one adult and 1000 mg in another did not cause acute toxicity.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) AURANOFIN
    a) ORAL RECOMMENDED DOSE: The typical adult dose is 6 mg/day in either one dose or two divided doses. If response is inadequate, the dose may be increased to 9 mg/day (3 mg three times daily) after six months. The medication should be discontinued after 3 months if the 9 mg/day dose does not produce an adequate response (Prod Info RIDAURA(R) oral capsules, 2007).
    2) AUROTHIOGLUCOSE
    a) The manufacturing of aurothioglucose was discontinued for business reasons in May 2002. The data in this evaluation are included for completeness only.
    b) A typical adult dose is given in injections once per week. This dose might be 10 mg intramuscularly for the first week, 25 mg the second week, and 25 to 50 mg each week thereafter (Prod Info Solganal(R), aurothioglucose, 1996).
    c) If no response is seen after a 1 gram dose, some suggest that therapy should be discontinued. Onset of effects are slow; sometimes 2 to 24 months is necessary for an effect. The dose may be decreased as a response is reached (Prod Info Solganal(R), aurothioglucose, 1996).
    3) GOLD SODIUM THIOMALATE
    a) RECOMMENDED DOSE: Initial treatment: 10 mg IM 1st week, 25 mg IM 2nd week, then 25 mg to 50 mg IM weekly until clinical response is achieved, toxicity develops, or the cumulative dose reaches 1 g. Failure of initial treatment: If a patient does not improve during initial treatment (cumulative dose of 1 gram), use one of the following courses of therapy: 1) Discontinue treatment; 2) Continue 25 mg to 50 mg for an additional 10 weeks; 3) Increased dose at increments of 10 mg every 1 to 4 weeks (not to exceed 100 mg as a single injection). If no significant improvement or toxicity develops, therapy should be discontinued. Maintenance therapy: 25 to 50 mg every 3rd or 4th week for 2 to 20 weeks, or indefinitely (Prod Info gold sodium thiomalate IM injection, 2005).
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) AURANOFIN
    a) The safety and efficacy of auranofin in the pediatric population has not been established (Prod Info RIDAURA(R) oral capsules, 2007).
    b) Doses up to 0.2 mg/kg/day (up to 6 mg/day) have been reported in children with juvenile rheumatoid arthritis (Giannini et al, 1983; Kvien et al, 1986).
    2) AUROTHIOGLUCOSE -
    a) The manufacturing of aurothioglucose was discontinued for business reasons in May 2002. The data in this evaluation are included for completeness only.
    b) In children 6 to 12 years old, the usual dose of aurothioglucose is one-fourth of the adult dose, depending on body weight. The dose should not exceed 25 mg/dose (Prod Info Solganal(R), 1997).
    3) GOLD SODIUM THIOMALATE
    a) RECOMMENDED DOSE: Start with test dose 10 mg IM, then give 1 mg/kg (maximum 50 mg/dose) IM weekly for 20 weeks; maintenance dose is 1 mg/kg IM (maximum 50 mg/dose) every 2-4 weeks. Cumulative dose for initial therapy 1 g (Prod Info gold sodium thiomalate IM injection, 2005).

Maximum Tolerated Exposure

    A) ACUTE
    1) TOXIC DOSE - There appears to be little correlation between total gold dose and toxicity. In a summary of 20 cases of toxicity from 1940 to 1950, the cumulative toxic dose was recorded as from 230 milligrams to 10 grams of each gold salt (McCarty et al, 1962).
    2) Pik et al (1985) reported on two cases of inadvertent intramuscular aurothioglucose overdose in which the patients received 1000 milligrams and 500 milligrams, respectively. One patient was asymptomatic. The second patient developed elevated liver enzymes. She recovered uneventfully without treatment (Pik et al, 1985).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) A 49-year-old woman with rheumatoid arthritis developed prolonged cholestasis and ductopenia 3 weeks after receiving intramuscular injections of sodium aurothiopropanolsulfonate (a cumulative dose of 600 mg [400 mg of this dose administered in less than a week]). Gold concentrations in hair (6 days post-admission), blood, and urine were 0.8 nmol/g, 20.4 mcmol/L, and 9.80 mcmol/L, respectively (Basset et al, 2003).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAMUSCULAR)RAT:
    1) 35 mg/kg
    B) LD50- (SUBCUTANEOUS)MOUSE:
    1) 400 mg/kg
    C) LD50- (INTRAMUSCULAR)MOUSE:
    1) 800 mg/kg
    D) LD50- (SUBCUTANEOUS)MOUSE:
    1) 930 mg/kg
    E) LD50- (INTRAMUSCULAR)RAT:
    1) 440 mg/kg
    F) LD50- (SUBCUTANEOUS)RAT:
    1) 303 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The mechanism of action of the gold compounds is unknown. It is hypothesized that gold is taken up by macrophages, resulting in inhibition of phagocytosis and of lysosomal enzymes.
    B) Gold is entrained in lysosomes and phagosomes in the synovial membrane, kidney, mesentery, skin, and other tissues. It does not affect the release of lysosomal hydrolases; rather, it inhibits their enzymatic activities.
    C) Gold has been shown to suppress the anaphylactic release of histamine more effectively than the glucocorticoids; it also prevents prostaglandin synthesis in vitro (Gilman et al, 1990).

Toxicologic Mechanism

    A) Thrombocytopenia may be due to direct bone marrow depression or an immunologic reaction with destruction of circulating platelets (Kozloff et al, 1979). Thrombocytopenia occurs in about 1% of treated patients, and in rare events, leukopenia, agranulocytosis and aplastic anemia can occur (Gilman et al, 1990).
    B) Heavy metal toxicity on hemopoietic function may be mediated via blockage of enzyme reactive sulfhydryl groups. If this is true, removal of gold is not as important as reversing the inhibition of the enzymes (Kozloff et al, 1979).
    C) Gold has been shown to inhibit pyruvate oxidase in low concentrations (Hazlett & Yendt, 1958).
    D) THE PROTEINURIA AND NEPHROTIC SYNDROME - produced by gold consists of an immune-complex glomerulonephritis with granular deposits along the basement membrane.
    1) The pathogenesis of this is not certain, but gold may act as a hapten and generate the production of antibodies, with deposition of the immune complex in the glomerular subepithelium.
    2) Another hypothesis is that antibodies are formed against damaged tubular structures, particularly mitochondria, providing immune complexes for the glomerular deposits (Klaassen et al, 1986).
    E) The differing excretory patterns of gold thiomalate and auranofin may account for their unique toxicity profiles.
    1) Since the majority of auranofin is excreted by the enteric route, and most of the administered dose of gold sodium thiomalate is excreted renally, it is not surprising that toxicity associated with auranofin is primarily gastroenterological whereas more renal toxicity is associated with gold sodium thiomalate (Blocka et al, 1986).
    F) Rare reports of encephalitis, peripheral neuritis, hepatitis, pulmonary infiltrates, and vasomotor crisis have been observed with gold therapy (Gilman et al, 1990).

Physicochemical

Molecular Weight

    A) GOLD SODIUM THIOMALATE: 390.07 (Cohen, 1988)
    B) GOLD SODIUM THIOGLUCOSE: 490.12 (Budavari, 1996)
    C) SODIUM AUROTHIOSULFATE: 526.2 (Reynolds, 2000)

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