Drugs 27: 378-424 (1984) 0012-6667/84/0500-0378/$23.50/0 © ADiS Press Limited All rights reserved

Auranofin A Preliminary Review of its Pharmacological Properties and Therapeutic Use in Rheumatoid Arthritis

M. ChajJman, R.N. Brogden, R.C. Heel, T.M. Speight and G.s. Avery ADIS Drug Information Services, Auckland

Various sections of the manuscript reviewed by: K. Bllndillll, Deutsche K1inik fUr Diag­ nostik. Wiesbaden, West Germany; I.L. Bontll, Department of Pharmacology, Erasmus Universiteit Rotterdam, Rotterdam, Holland; D.E. Furst, Division of Rheumatology, University ofIowa, Iowa City, Iowa, USA; N.L. Gottlieb, Department of Medicine, School of Medicine. University of Miami, Miami, Florida, USA; I. Hilfttrom, Department of Medicine Ill. Institute of SOdersjukhuset, Stockholm, Sweden; F.D. Hllrt, Harley Street, London. England; M. Hllrth, Section of Rheumatology, Department of Medicine, Uni­ versity of Western Ontario, London, Canada; P.E. Lipsky, Department of Internal Med­ icine. University of Texas Health Science Center at Dallas, Dallas, Texas, USA; A. Lorber, Memorial Hospital Medical Center of Long Beach, Long Beach, California, USA; O.L. Meyers, Department of Medicine, University of Cape Town, South Africa; D. Schorn, Van der Walt Street, Pretoria, South Africa; S.H. Roth, Phoenix Arthritis Center, Phoe­ nix. Arizona, USA; B. WOiIlCh, Meir General Hospital, Kfar-Saba, Israel.

Contents

Summary ...... 379 I. Pharmacodynamic Studies ...... 383 1.1 Anti-Inflammatory Activity ...... 384 1.2 Effects on Humoral Immune Response ...... 384 1.2.1 Animal Studies ...... 384 1.2.2 Human Studies ...... 384 1.3 In Vitro Effects on Cell-Mediated Immunity ...... 385 1.3.1 Effects on Polymorphonuclear Leucocyte Activity ...... 386 1.3.2 Effects on Mononuclear Leucocyte Activity ...... 388 1.4 In Vitro Effects on DNA. RNA. and Protein Synthesis ...... 389 1.5 Other Effects ...... 390 1.5.1 In Vitro Effect on Platelet Aggregation ...... 390 1.5.2 In Vitro Effect on Prostaglandin Activity ...... 390 1.5.3 Antitumour Activity In Vitro ...... 390 1.5.4 Effects on Copper and Zinc Metabolism ...... 390 1.6 Mechanism of Action ...... 391 1.7 Toxicology Studies ...... 392 1.7.1 Acute Toxicity ...... 392 1. 7.2 Subacute and Chronic Toxicity ...... 392 1.7.3 Effects on Reproduction ...... 393 Auranofin: A Preliminary Review 379

2. Pharmacokinetics of Auranofin ...... 393 2.1 Absorption ...... 393 2.2 Plasma Concentrations ...... 393 2.3 Distribution ...... 395 2.3.1 Extracellular Distribution ...... 395 2.3.2 Blood Cell Distribution ...... 396 2.3.3 Tissue Distribution ...... 397 2.3.4 Gold Retention ...... 397 2.4 Excretion ...... 397 3. Therapeutic Trials ...... 399 3.1 Rheumatoid Arthritis ...... 400 3.1.1 Open Studies ...... 400 3.1.2 Dose Establishment Studies ...... 40 I 3.1.3 Auranofin Compared with Placebo ...... 404 3.1.4 Comparisons with Sodium Aurothiomalate ...... 404 3.1.5 Comparisons with Other Agents ...... 408 3.1.6 Effects of Auranofin on the Radiographically Detected Progression of Rheumatoid Disease ...... 409 3.2 Juvenile Rheumatoid Arthritis ...... 412 3.3 Other Areas of Use ...... 412 4. Side Effects ...... 412 4.1 Gastrointestinal Effects ...... 412 4.2 Haematological Effects ...... 413 4.3 Renal Effects ...... 414 4.4 Mucocutaneous Effects ...... 414 4.5 Other Reactions ...... 414 5. Dosage and Administration ...... 415 6. The Place of Auranofin in Therapy ...... 415

Summary Synopsis: Auranofin l is the first orally active gold compound for the treatment of rheu­ matoid arthritis. Like other chrysotherapeutic agents. its exact mechanism of action is unknown. but it probably acts via immunological mechanisms and alteration oflysosomal enzyme activity. Although long term clinical experience with auranofin is limited. its ejJicacy appears to approach that of sodium aurothiomalate. Further comparative studies with aurothio­ glucose. hydroxychloroquine and D-penicillamine are required before definitive statements can be made regarding the relative efficacy of auranofin and these agents. While patients have demonstrated clinical remission of rheumatoid arthritis in response to auranofin therapy, radiological studies have been inconclusive regarding its ~ffect on the occurrence or progression of erosive lesions. Aurano/in is relatively well tolerated in most patients. but diarrhoea, skin rash, and pruritus are sometimes troublesome, and thrombocytopenia and proteinuria are poten­ tially serious side effects which may occur during therapy. Whereas mucocutaneous side effects are more frequent with injectable gold compounds, gastrointestinal reactions are the most common adverse e.ffect seen with auranofin. The frequency of side ({fects has heen similar with auranofin and sodium aurothiomalate. hut they are generally less severe with auranofin. While some of the side effects are controlled by a reduction in dosage. temporary or permanent withdrawal of auranofin may he necessary. Auranof/Il is clearly a useful addition to the limited list of agents with disease-modi­ /i'ing potential presently availablefor the treatment of rheumatoid arthritis. It will douht·

I 'Ridaura' (Smith Kline & French). Auranofin: A Preliminary Review 380

less generate much interest as its final place in therapy becomes better defined through additional well-designed studies and wider clinical experience.

Pharmacodynamic Studies: Auranofin has been demonstrated to have anti-inflam­ matory activity as evidenced by significant (59 to 70%) inhibition of carrageenan- or kaolin-induced paw oedema in rats and UV -induced erythema in guinea-pigs. Inhibition of passive cutaneous anaphylactic reactions and adjuvant arthritis have also been dem­ onstrated in rats. In an in vitro model of humoral immune response, auranofin has produced inhibition of haemolytic plaque-forming cells in mouse spleen culture. Auranofin has also been shown to inhibit anti-human IgE-induced release of histamine from fragmented, passively sensitised primate lung and immunologically mediated release of slow reactive substance of anaphylaxis - both in vitro models of immediate hypersensitivity. In vivo. auranofin tOmg gold/kg daily inhibited antibody production in sensitised rats, and decreased the ability of immune sera to participate in antibody-dependent cellular cytotoxicity and antibody-dependent complement lysis. Auranofin 2.5, 5 and tOmg gold/ kg produced an increase in delayed hypersensitivity without alteration of humoral response. Auranofin is capable of decreasing rheumatoid factor titre and restoring normal im­ munoglobulin concentrations in patients with rheumatoid arthritis, although the suppres­ sion is generally of a lower magnitude .than that seen following sodium aurothiomalate treatment. Numerous in vivo and in vitro tests have been performed to determine the effects of auranofin on cell-mediated immunity. In mice, auranofin was capable of stimulation of compromised oxazolone-induced contact sensitivity and delayed hypersensitivity. Most of the in vitro testing of the effects of auranofin on polymorphonuclear cell activity has been performed with cells of human origin. Human neutrophil chemotaxis was shown to be significantly impaired when cells were incubated with various concentrations of auranofin and exposed to endotoxin-activated serum. Auranofin 2.5/Lg gold/ml decreased (p < 0.0 I) human polymorphonuclear cell phagocytosis of Candida albicans. The in vitro effects of auranofin on superoxide production as determined by chemiluminescence have been variable, with both decreases and increases in production having been demon­ strated. In polymorphonuclear cells from patients treated with auranofin 6mg daily for 23 weeks. chemiluminescence was enhanced, thus casting doubt on the clinical signifi­ cance of decreased superoxide production in vitro. Auranofin 2 and 4/Lg gold/ml decreased formyl-methionyl-Ieucyl-phenylalanine (FMLP)-induced !3-glucuronidase release from human polymorphonuclear leucocytes by 35 and 62%. respectively. However, at a lower concentration (I/Lg gold/ml), auranofin enhanced lysozyme release. In human polymorphonuclear leucocytes incubated with aur­ anofin 0.5 or 1.0/Lg gold/ml and exposed to IgG-rheumatoid factor immune complexes, release of !3-glucuronidase, acid phosphatase and lysozyme was almost completely sup­ pressed. Polymorphonuclear cells obtained from patients with rheumatoid arthritis who responded clinically to auranofin exhibited a 43% decrease in FMLP-induced lysozyme release, while cells from non-responding patients showed no change in lysozyme release. The mechanism of inhibition of lysosomal enzyme release by auranofin is unclear, but may depend on blockade of cell membrane transport or increased intracellular concen­ trations of cyclic AMP. In human mononuclear phagocytic cells, as in polymorphonuclear leucocytes, the ef­ fect of auranofin on superoxide production or release in vitro has been variable, being suppressed by 1.5 to 2.5/Lg gold/ml and increased at lower concentrations. In vitro, human synovial macrophage phagocytic activity was suppressed 26% by auranofin to mg/mt. In I'itro. auranofin has inhibited human lymphocyte and monocyte antibody-depend­ ent cellular cytotoxicity. Auranofin has also demonstrated possible cytostatic activity as evidenced by decreased synthesis of deoxyribonucleic acids, ribonucleic acids and protein in lymphocytes from patients treated with auranofin, and in in vitro human cell cultures Auranofin: A Preliminary Review 381

of HeLa carcinoma, RAJI lymphoma, Epstein Barr virus-transformed lymphocytes and other human tumour models. Auranofin stimulated natural killer cell activity against RAJ! and HAE-60 target cells, induced morphological changes in HeLa cells, and inhib­ ited lymphocytic P388 tumour growth in mice. In vitro. auranofin IOltg gold/ml inhibited platelet aggregation induced by ADP, ad­ renaline (epinephrine), or collagen. The same concentration of auranofin gold was also shown to inhibit prostaglandin EI activity 50 to 70% in rat ovaries. Like other gold compounds, auranofin has been shown to decrease serum copper concentrations in la­ boratory animals and humans coincident with improvement in rheumatic symptoms. In common with other forms of gold therapy, the exact mechanism of action of aur­ anofin in rheumatoid arthritis is unknown. However, it most likely acts through one or more of its immunomodulating effects and/or its inhibition of lysosomal enzyme activity or release.

Pharmacokinetic Studies: On the basis of urinary and faecal recovery data, auranofin is approximately 25% absorbed following oral administration in patients with rheumatoid arthritis. The location and mechanism of auranofin absorption are unknown. Whole blood auranofin gold concentrations are haematocrit dependent, whereas concomitant plasma or serum concentrations are approximately equal. Steady-state plasma gold concentra­ tions are dose dependent and ranged from 20 to 100 Itg/ml 8 to 12 weeks following initiation of treatment with auranofin 2 to 9mg daily, respectively. No consistent cor­ relation has been shown to exist between auranofin whole blood gold concentrations and therapeutic efficacy or toxicity. The apparent volume of distribution of auranofin has not been reported and the intracellular distribution of the drug has not been studied. In whole blood, auranofin gold is 60% distributed to plasma, 37% distributed intracellularly, and 3% distributed to cellular membranes. In serum, 82% of auranofin gold is bound to albumin and 18% to globulin. Auranofin gold penetrates the synovial fluid of patients with rheumatoid arth­ ritis at a concentration ratio of approximately 1 to 1.7 that of whole blood. It is not known if it is the free gold, the fraction bound to albumin, or that associated with blood cells which is pharmacologically active. Retention of gold associated with auranofin treatment appears to be minimal. In rats, organ tissue gold concentrations are 1.4 to 3% of those observed following administration of sodium aurothiomalate. Unlike with parenteral gold compounds, skin punch biopsies in man have rarely demonstrated detectable gold concentrations following long term treatment with auranofin. However, oral and parenteral gold compounds produce min­ imal similar hair and nail gold concentrations following prolonged therapy. Following 6 months of continuous treatment, the terminal serum half-life of a single dose of auranofin is about 25 days. The mean terminal total body half-life is 57 to 81 days. About 88% of a dose of auranofin is excreted in the faeces and 12% via the kidneys following long term therapy. Renal and enteric clearances have been determined to range from 0.064 to 0.261 ml/h/kg and 0.030 to 0.472 ml/h/kg, respectively.

Therapeutic Trials: Most of the clinical experience with auranofin is derived from a series of short term open and controlled studies, many of which have been designed both to assess the efficacy of the drug and to establish dosage guidelines. Unfortunately, many of the studies which have compared auranofin with other disease-modifying agents have released only preliminary findings and/or have been published in abstract form only. Therefore, definitive data regarding the long term efficacy and tolerability of auranofin compared with other disease-modifying drugs are limited. The open studies of auranofin have generally shown it to be an effective and well­ tolerated agent for the treatment of rheumatoid arthritis. In most studies auranofin (usu­ ally 6mg daily) reduced duration of morning stiffness, erythrocyte sedimentation rate, and number of tender and/or swollen joints. Side effects due to auranofin were usually mild and easily managed, only occasionally necessitating drug withdrawal. Auranofin: A Preliminary Review 382

In the dose establishment studies, auranofin 2mg daily was similar in efficacy to dosages of auranofin of 3 or 6mg daily. Higher dosages (> 6mg daily) were generally associated with more rapid improvement in laboratory and clinical manifestations of rheumatoid arthritis, but also with more frequent and/or severe lower gastrointestinal effects. Lower dosages of auranofin « 2mg daily) often resulted in poor antirheumatic efficacy. There is substantial evidence that once-daily dosage provides efficacy equal to that of divided dosages, and is not associated with a greater incidence of toxicity. In patients with rheumatoid arthritis, auranofin was shown to be superior to placebo in practically all assessment criteria. Comparative trials of auranofin and sodium auro­ thiomalate in rheumatoid arthritis have generally shown auranofin to be somewhat less effective. but also decidedly less toxic. Inefficacy was the most common cause of with­ drawal among auranofin-treated patients, whereas toxicity was the main reason for dis­ continuation of sodium aurothiomalate. In patients with rheumatoid arthritis, the effi­ cacy of auranofin appears to be similar to that of D-penicillamine, but somewhat less than that of aurothiopropanolsulphonate. However, auranofin generally causes fewer side effects than either agent. Due to the methodological difficulties and differences associated with various meth­ ods of radiographic measurement of disease progression, the potential of auranofin to alter the joint narrowing and bone erosion of rheumatoid arthritis is not yet clearly de­ fined; this is an important area for further study. One small therapeutic trial in patients with juvenile rheumatoid arthritis has shown encouraging results with significant improvements in number and severity of swollen joints. pain on motion, tenderness of joints, and erythrocyte sedimentation rate. Double­ blind controlled studies are indicated to further clarify the role of auranofin in the treat­ ment of this disease.

Side Effects: The most frequent side effects of auranofin are gastrointestinal (about 50% of patients overall), about 30 to 40% of all patients taking auranofin experiencing loose stools or diarrhoea. Diarrhoea due to auranofin may only be transient, and will usually respond to temporary discontinuation, reduction in dose, or symptomatic treat­ ment. Although they occur infrequently, anaemia, leucopenia, eosinophilia and thrombo­ cytopenia have been reported with auranofin usage. Laboratory monitoring for these problems is essential. All have been totally reversible upon discontinuation of auranofin. Proteinuria (rarely progressing to the nephrotic syndrome) has been reported with auranofin. Mild proteinuria has sometimes reversed with simple dose reduction, although discontinuation of drug has been required in some cases. Up to 6 months may be required for complete reversal of proteinuria following discontinuation of auranofin. Mucocutaneous reactions have also been frequent (about 30 to 40% of overall patients) in auranofin trials. Approximately 18 to 24% of all patients have experienced rash and/ or pruritus. Stomatitis occurs with auranofin, but is relatively infrequent. Alopecia and conjunctivitis have also been reported, their respective incidences being 2 and 10%. Mucocutaneous reactions can readily be reversed with dose reduction or discontinuation of therapy.

Dosage and Administration: In most patients the recommended dose of auranofin is 6mg administered as a single daily dose. The effects of significant renal or hepatic dys­ function on the disposition of auranofin are not known, and its administration is not advised in patients with abnormal liver or kidney function. Patients should be frequently monitored for gastrointestinal and mucocutaneous side effects; complete blood counts and urinalysis should be performed at at least monthly intervals. Management of gold toxicity is dependent upon the type and severity of the reaction. Auranofin: A Preliminary Review 383

1. Pharmacodynamic Studies Interpretation of in vitro or animal data as they relate to the pharmacodynamic effects of auranofin Auranofin is an alkyl phosphine gold coordina­ or other gold compounds in humans should be tion complex, containing 29% gold by weight made with considerable caution (Lorber, 1983a,b; (Bernhard, 1982a; Menninger and Burkhardt, Sliwinski and Guertin, 1982). Agents such as aur­ 1983b; Sutton et aI., 1983; Walz, 1979) [fig. 1]. anofin and sodium aurothiomalate exist for only Auranofin is active in standard animal models brief periods in vivo as intact molecules (Furst, of inflammation, and in inhibiting lysosomal en­ 1983; lellum et aI., 1979; Lewis and Walz, 1982), zyme release from animal and human leucocytes. and this cannot be taken into account in in vitro Both auranofin and sodium aurothiomalate inhibit tests. Also, culture media or drug vehicle constit­ cell-mediated immunity, probably due to inhibi­ uents may react with a drug or influence its activ­ tion of monocyte-macrophage dependent immune ity, possibly creating artifactual effects on cellular reactions (Hanna et aI., 1983; Harth, 1983; Lipsky functions (Lorber, 1983b). Finally, to conclude that and Ziff, 1977). While both agents affect B- and T­ in vitro effects of gold compounds have clinical sig­ lymphocyte function in vitro, auranofin appears to nificance in man, these effects should be observed alter T-Iymphocyte activity more than that of B­ with concentrations attainable in treated patients lymphocytes, whereas sodium aurothiomalate (Lipsky and Ziff, 1977). Although it is not known seems to exert its greatest effects on B-Iymphocyte which fraction of total body gold is that which is function (Lorber et aI., 1981). pharmacologically active (see section 2.3), concen­ trations of auranofin and other gold compounds utilised in in vitro tests have often far exceeded those achievable or desirable in man (Lewis and Walz, 1982) [section 2.2], and most of the inves­ CH20COCH3 tigations in laboratory animals have involved S_AU_P(C2H3h greater dosages than those used to treat patients with rheumatoid arthritis (Lorber, 1983b). OGaGH 3 GH 3GOaG Sliwinski and Guertin (1982) have presented evidence that the portion of auranofin which is ac­ OGaCH 3 Auranofin tive in some in vitro models of human neutrophil function may be that which is not protein bound, GOONa, H-C-S-Au whereas the portion of sodium aurothiomalate I H-C-H, which is active in the same tests is the protein­ GaONa bound fraction. In contrast, more recent data from Sodium aurothiomalate Lorber et al. (1983a) have indicated that the active (gold sodium thiomalate) portion of both drugs is that which is unbound, and that the amount of unbound serum gold HO-9-H--1 correlates with the degree of suppression of H-C-~H I I 0 lymphocyte mitogen response and phagocytosis, OH-C-~ H-r,-OH and respiration of circulating polymorphonuclear H-G, leucocytes from patients with rheumatoid arthritis H-«-S-Au (see section 2.3.1). H The validity of many of the in vitro compari­ Aurothioglucose sons of auranofin and sodium aurothiomalate may be in doubt until the relationships between drug Fig. 1. Structural formulae of auranofin, sodium aurothiomalate distribution and immunological effect are more and aurothioglucose. clearly defined for both agents. Auranofin: A Preliminary Review 384

1.1 Anti-Inflammatory Activity dependent cellular cytotoxicity in rats sensitised with mouse L929 fibroblasts and in adjuvant arth­ Auranofin possesses anti-inflammatory activity ritic rats (Walz et aI., 1979a, 1982b). Immune sera as evidenced by inhibition of carrageenan- (Walz (anti-L929) from auranofin-treated rats exhibited a et aI., 1982a) or kaolin-induced (Lewis et aI., 1980) substantial decrease in ability to mediate antibody­ paw oedema in rats, inhibition of ultraviolet­ dependent complement lysis. induced erythema in guinea-pigs (Lewis et aI., Auranofin (lOmg gold/kg/day) suppressed 7S 1980), and inhibition of passive cutaneous ana­ haemagglutinin antibody responses to sheep red phylactic reactions and adjuvant-induced arthritis blood cells in adjuvant arthritis rats (Walz et aI., in rats (Hertz et aI., 1983; Lewis et aI., 1980; Walz 1976, I 982a), but not in sensitised mice (Walz and et aI., 1976). Griswold, 1978). Auranofin 2.5, 5 and IOmg gold/ At a dosage equivalent to 20mg of gold/kg, aur­ kg stimulated delayed hypersensitivity of mice to anofin produced a greater inhibition of carra­ sheep red blood cells, without altering humoral re­ geenan-induced paw oedema (50 to 70%) than sod­ sponse (Walz and Griswold, 1978). ium aurothiomalate « 40%) at dosages which Auranofin can suppress animal humoral im­ produced I O-fold higher serum gold concentra­ mune responses in a variety of assay systems tions. The effect of auranofin is independent of whereas sodium aurothiomalate is most often in­ adrenal function, whereas that of sodium auro­ active or enhances immune responses in these sys­ thiomalate is partially adrenal dependent (Walz et tems (Walz et aI., 1982a,b) [table I]. aI., I 982a). Kaolin-induced rat paw oedema was inhibited 1.2.2 Human Studies to a greater extent by auranofin than by sodium The therapeutic use of parenteral gold com­ aurothiomalate, although ultraviolet erythema in pounds has been shown to be associated with de­ guinea-pigs was suppressed to a similar extent by creases in immunoglobulin concentrations and both drugs (Lewis et aI., 1980). Auranofin at doses rheumatoid factor titres (Davis, 1983; Harth, 1980). equivalent to 4, 10 and 20mg gold/kg daily pro­ Similar effects have been observed during long term duced a dose-related suppression of primary and auranofin therapy in patients with rheumatoid secondary lesions of adjuvant arthritis in rats, sim­ arthritis (Bergl6f et aI., 1978; Davis, 1983; Finkel­ ilar to that with sodium aurothiomalate 10mg gold/ stein et aI., 1976; Lorber et aI., 1979a, 1981). kg. However, the parenteral gold compound re­ Thus, Finkelstein et al. (1976) noted a 26.5% sulted in a greater decrease in percentage survival decrease in l'-globulin concentration after 12 weeks' (75%) at the intermediate dosage (Walz et aI., 1976). administration of auranofin 6 or 9mg daily to patients with rheumatoid arthritis, and Finkelstein 1.2 Effects on Humoral Immune Response et al. (1979) recorded decreases of 13 and 49% in mean total IgG and IgM-rheumatoid factor con­ 1.2.1 Animal Studies centrations, respectively, after 3 months' treatment In vitro, auranofin alters humoral immunity as with auranofin (mean blood gold concentration 0.55 evidenced by the decrease in haemolysin plaque­ ILg/ml). In other studies, auranofin 6mg daily for forming cells in mouse spleen cultures plated with up to I year failed to alter IgG (BerglOf et aI., 1978; sheep red blood cells, and in immunologically me­ Hafstr6m, 1983; Lorber et aI., 1979a, 1981). Posi­ diated release of slow reactive substance of ana­ tive correlations have existed between the daily phylaxis from fragmented primate lung (Walz et dosage of auranofin and the whole blood or serum al.. 1976). gold concentration and the magnitude of suppres­ In vivo studies in animal models have demon­ sion of abnormally high immunoglobulin concen­ strated that auranofin is capable of decreasing the trations (Finkelstein et aI., 1976, 1979; Lorber et ability of immune sera to participate in antibody- al.. 1979a). Decreases in rheumatoid factor titres Auranofin: A Preliminary Review 385

Table I. Summary of comparative in vitro and in vivo effects of auranofin (A F) and sodium aurothiomalate (ATM) on humoral immunity (adapted from Walz et aI., 1982a)

Reference Assay Species Effect Concentrations

AF ATM AF ATM

In vitro Walz et al. (1979a) HPFC Mouse At 1,10 and 100 Only at 100 jlmol/L jlmol/L

In vivo Walz and Griswold Haemagglutinin titres Mouse 0.625-10.0mg Au/kg 0.625-10.0mg Au/kg (1978) during delayed hypersensitivity Delayed hypersensitivity Mouse At 2.5, 5.0 and At 5.0mg Au/kg only 10.0mg Au/kg

Walz et al. (1976) HPFC Rat 10mg Au/kg/day 5mg Au/kg/day x 4d x 4d 7S anti-SRBC antibody Rat 10mg Au/kg/day 5mg Au/kg/day titre x 4d x 4d

Walz et al. (1979a) HPFC Mouse Initial j 20.0mg Au/kg/day 20mg Au/kg/day later 1 x 4d x 4d ADCC antibody Rat 10mg Au/kg/day 5mg Au/kg/day x 4d x 4d ADCL antibody Rat 10mg Au/kg/day 5mg Au/kg/day x 4d x 4d

Walz et al. (1982b) 7S and 19S Rat j 7S titres 10mg Au/kg/day 9.3mg Au/kg/day haemagglutination titres 119S titres x 4d x 4d

Abbreviations: HPFC = haemolytic plaque-forming cells; SRBC = sheep red blood cells; ADCC = antibody-dependent cellular cyto- toxicity; ADCL = antibody-dependent complement lysis; t = increase; j = decrease; - = no change.

and an increase in the albumin/globulin ratio ac­ arthritis treated with auranofin 6mg daily for an companied clinical improvement in 8 patients average of 45 weeks (Lorber et ai., I 979a). Skin studied by Berglo[ et ai. (1978), but other studies reaction to rechallenge with dinitrochlorobenzene have not demonstrated decreased rheumatoid fac­ was prevented completely in 9 of 15 patients and tor titres with auranofin treatment (Hafstrom, 1983; partially in a further 2 patients. In contrast, thera­ Lorber et ai., 1979a, 1981). Auranofin 6mg daily peutic doses of sodium aurothiomalate failed to decreased concentrations of IgM and IgA signifi­ prevent a reaction in 13 of 15 patients in a parallel cantlyafter 16,26 and 52 weeks of therapy (Lorber group. Despite the inhibition of T-Iymphocyte et ai., 1981); however, comparative studies (Kee­ function by auranofin, there was no evidence of an gan et ai., 1983; Lorber et ai. 1979a; 1981) have increased incidence of local or systemic infectious indicated that decreases in immunoglobulins and disease. rheumatoid factor titre may be smaller with aur­ anofin than with sodium aurothiomalate (serum or I.3 In Vitro Effects on Cell-Mediated blood gold concentration ~ 3 ,",g/ml). Immunity Dinitrochlorobenzene was administered to as­ sess skin test response in patients with rheumatoid Auranofin and sodium aurothiomalate have Auranofin: A Preliminary Review 386

been shown to affect cell-mediated immunity as trations of approximately 0.5 JLg/ml) [Finkelstein determined by their influence on oxazolone-in­ et ai., 1982b]. Although further data are required duced contact sensitivity and delayed hypersensi­ to confirm these findings, auranofin appears to re­ tivity to sheep red blood cells in mice (Walz and store depressed antibody-dependent cellular cyto­ Griswold, 1978; Walz, 1981), and experimental al­ toxicity in vivo, and inhibit it in in vitro settings. lergic encephalomyelitis in rats (Walz et ai., I 982a). In low concentrations (0.25 to 0.50JLg gold/ml), Auranofin (1.25 to IOmg gold/kg) and sodium auranofin has been shown to cause marked in vitro aurothiomalate (5 and 10mg gold/kg) were capable stimulation of human natural killer cell activity of stimulating compromised oxazolone-induced against RAJ!, K-562 and HAE-60 target cells. contact sensitivity, but neither agent significantly However, natural killer cell activity against these altered the uncompromised response in normal targets was decreased by higher auranofin concen­ mice and only auranofin (5mg gold/kg) stimulated trations (~ 1.0JLg gold/ml) [Harris et ai., 1983; Rus­ immune response in mice which had been im­ sell et ai., 1982]. In mostly higher concentrations munosuppressed with methotrexate. In stimula­ (0.1 to 1O.0JLg gold/ml), auranofin suppressed both tion of delayed hypersensitivity to sheep red blood T- and B-Iymphocyte proliferative responses in vitro cells (also see table I), similar activity occurred at via stimulation of suppressor cell activity (Koba­ concentrations of auranofin which were one-half yashi et ai., 1982). those of sodium aurothiomalate. In rats, auranofin In phytohaemagglutinin-stimulated human and sodium aurothiomalate inhibited the onset (but lymphocytes, auranofin 1JLg gold/ml inhibited the not the cumulative incidence) of experimental al­ incorporation of 3H-thymidine into DNA by 98% lergic encephalomyelitis (Walz et ai., 1982a). and 16% when present for 72 and 2 hours, respec­ Antibody-dependent cellular cytotoxicity me­ tively (Finkelstein et ai., I 977a). Protein synthesis diated by rat peripheral blood polymorphonuclear was also significantly (88%) blunted following 72 leucocytes was markedly decreased (~ 94%) by aur­ hours of incubation with auranofin. Since the in­ anofin 2JLg gold/ml, whereas the process was shown hibition induced by auranofin could not be re­ to be enhanced in the presence of auranofin 0.2JLg versed by cell washing, it may have been due to gold/ml or less (Di Martino and Walz, 1980). The interference with 'normal' lymphocyte membrane cells had been pretreated with auranofin and then transport activity, as evidenced by inhibition of washed prior to testing, indicating that this was a membrane transport of 3H-thymidine. However, direct inhibitory effect on the polymorphonuclear similar studies did not show decreased membrane cells, and not on the antibody or target cell com­ transport of 3H-2-deoxy-D-glucose (Simon et ai., ponents of the reaction. 1979a,b) [section 1.4]. Phytohaemagglutinin mi­ The in vitro effects of auranofin on lymphocyte togen stimulation was not inhibited by sodium au­ antibody-dependent cellular cytotoxicity appear rothiosulphate IJLg gold/mi. to be concentration dependent, and perhaps also Lymphocytes from patients with rheumatoid dependent on the method of cell exposure to the arthritis who were treated with auranofin 3mg twice drug. In vitro, human lymphocyte antibody-de­ or thrice daily for 20 weeks produced an 80% pendent cellular cytotoxicity was affected only suppression of phytohaemagglutinin-stimulated in­ slightly by auranofin 0.25 to 1.0JLg gold/ml, but corporation of 3H-thymidine into DNA (Lorber, markedly to almost completely inhibited by higher 1983a; Lorber et ai., 1981). concentrations of 1 to 2.5JLg gold/ml (Finkelstein et ai., 1982b; Russell et ai., 1982). In vivo, de­ 1.3.1 Effects on Polymorphonuclear pressed baseline lymphocyte antibody-dependent Leucocyte Activity cellular cytotoxicity in patients with rheumatoid In polymorphonuclear cells isolated from arthritis was corrected by administration of aur­ healthy volunteers or patients with rheumatoid anofin 6mg daily (producing serum gold concen- arthritis, neutrophil chemotaxis in response to Auranofin: A Preliminary Review 387

endotoxin-activated serum was significantly im­ complex and 'frustrated' phagocytosis (where im­ paired by auranofin at concentrations as low as I mune complexes were fixed to micropore filters) to 4 Ilg/ml (Hafstrom et aI., 1983b; Schienberg et [Roisman et aI., 1982]. Chemiluminescence in­ aI., 1979) but neutrophil random migration was not duced by either particulate or soluble stimuli was affected (Hafstrom et aI., 1983b). In vitro neutro­ increased after human polymorphonuclear cell in­ phil chemotaxis in response to endotoxin-activated cubation with auranofin 1 to 2 Ilgjml, but de­ serum was stimulated in another study by a similar creased following incubation with auranofin 4 Ilgj concentration range of auranofin (approximately ml (Hafstrom et aI., 1982). Similarly, auranofin 6mg 0.7 to 7.0 Ilg/ml) [Marcolongo et aI., 1983]. Stimu­ daily for 23 weeks stimulated chemiluminescence lation of polymorphonuclear cell migration was in polymorphonuclear cells of patients with rheu­ demonstrated in cells from patients with rheuma­ matoid arthritis rather than inhibiting the process toid arthritis treated with auranofin 6mg daily for (Hafstrom et aI., 1983a,b). The variability ofthese 23 weeks (Hafstrom et aI., 1983a). findings may cast some doubt on their clinical sig­ Phagocytosis of Candida albicans by human nificance. If auranofin actually decreases the pro­ polymorphonuclear cells was shown to be de­ duction of superoxide radicals, the inhibition is creased (p < 0.01) by auranofin 0.5 to 2.51lg gold/ probably a result of a direct action of the drug rather ml (Davis et aI., 1982b). than a suppression of phagocytosis, as evidenced The oxidative metabolites produced during ac­ by its inhibition of chemiluminescence and super­ tivation of polymorphonuclear cells by particulate oxide production by soluble stimuli (Davis et aI., or soluble stimuli are collectively termed the 'res­ 1983; Hafstrom et aI., I 983b). There is some in piratory burst', and can be measured by use of a vitro evidence to indicate that auranofin inhibits chemiluminescence assay. Auranofin 0.5 to 2.5 Ilgj superoxide production in human polymorphonuc­ ml gold significantly decreased chemiluminescence lear cells by modulation of ligand-receptor cou­ in human polymorphonuclear leucocytes stimu­ pling and nicotinamide-adenine dinucleotide phos­ lated by zymosan (Davis et aI., 1982b) and de­ phate oxidase activity (Minta et aI., 1983). creased superoxide production during immune Auranofin has significantly decreased lysosomal

Table II. Summary of comparative studies of the in vitro effects of auranofin (AF) and sodium aurothiomalate (ATM) on poly­ morphonuclear leucocyte activity (adapted from Walz et aI., 1982a)

Reference Function Effect Gold concentrations (pg/ml)

AF ATM AF ATM

In rat polymorphonuclear cells Di Martino and Walz (1977) Lysosomal enzyme release ....b 0.2-20.0 20b

Di Martino and Walz (1980) ADCC ~. 2.0· 2.0

In human polymorphonuclear cells Davis et al. (1982b) Superoxide production 0.5-2.5 1.0-100.0 PhagocytOSiS 0.5-2.5 1.0-100.0

Roisman et al. (1982) Superoxide production l (47-72%) l (15%) 1.0 40.0

Wolach et al. (1981) Aggregation l (20-100%) ~ (35%) 1.0-4.0 40.0 Lysosomal enzyme release ~ ~ 2.0 200.0 a t at 0.2"g Au/mi. b ) at 0.2"g Au/ml. Abbreviations: ADCC = antibody-dependent cellular cytotoxicity; t = increase; l = decrease; .... = no change. Auranofin: A Preliminary Review 388

enzyme release to soluble and particulate stimuli aurothiomalate and aurothioglucose do not inhibit in most in vitro laboratory assessments (table II), lysosomal enzyme release, but inhibit enzyme ac­ although one group (Hafstrom et aI., 1983a) has tivity (Vernon-Roberts, 1979). noted a 'biphasic' effect on enzyme release. Aur­ Auranofin 1 to 4ILg gold/ml was shown to in­ anofin 2ILg gold/ml reduced formyl-methionyl-leu­ hibit FMLP-induced aggregation of cytochalasin B­ cyl-phenylalanine (FMLP)-induced lysozyme and treated human polymorphonuclear cells from 20 to {1-glucuronidase release by 35 and 62%, respec­ 100% (Wolach et aI., 1981, 1982), but did not in­ tively, in human polymorphonuclear leucocytes hibit polymorphonuclear cell aggregation in rabbits (Wolach et aI., 1981). A greater concentration of infused with zymosan-activated serum following 4ILg gold/ml reduced FMLP-induced secretion of the administration of auranofin 10 or 20 mg/kg/ lysozyme, {1-g1ucuronidase, myeloperoxidase and day for 3 days, thus shedding doubt on the sig­ lactoferrin 61.5,61.7,84.8, and 50.0%, respectively nificance of the in vitro findings (Wolach et aI., (Wolach et aI., 1982). Auranofin 4ILg gold/ml de­ 1982). In vitro adherence and aggregation (FMLP­ creased FMLP-stimulated lysozyme release by 26%, induced) of human polymorphonuclear cells were but a concentration of IlLg gold/ml increased re­ enhanced by auranofin 1 to 4 ILg/ml, but aggrega­ lease by 51 % (Hafstrom et aI., 1982, 1983b). A sim­ tion induced by leukotriene B4 was not influenced ilar biphasic response in {1-g1ucuronidase release (Hafstrom et aI., 1983a). also occurred when neutrophils were stimulated with FMLP. In the polymorphonuclear cells from 1.3.2 Effects on Mononuclear Leucocyte patients with rheumatoid arthritis who had dem­ Activity onstrated a clinical response to auranofin, FMLP­ The relative effects of auranofin and sodium induced lysozyme release was decreased 43%. aurothiomalate on mononuclear leucocyte activity Patients who had shown no response to the drug are summarised in table III. had no change in lysozyme release from baseline In rat mononuclear leucocytes, pretreatment values (Hafstrom et aI., 1982, 1983a,b). When hu­ with auranofin 2ILg gold/ml resulted in significant man polymorphonuclear leucocytes were exposed (p ~ 0.05) enhancement of mononuclear cell and in vitro to IgG-rheumatoid factor immune com­ target cell contact in the presence or absence of im­ plexes following incubation with auranofin 0.5 to mune sera (Di Martino and Walz, 1980). In human 1.01Lg gold/ml, the concentrations of {1-g1ucuroni­ mononuclear phagocytic cells isolated from peri­ dase, acid phosphatase and lysozyme released dur­ pheral blood of healthy volunteers and patients with ing immune complex phagocytosis were decreased rheumatoid arthritis, auranofin 1.5 to 2.51Lg gold/ 100, 80, and 30 to 100%, respectively (Finkelstein ml produced inhibition of FMLP-induced super­ et aI., I 977b, I 982a). oxide radical release (Davis et aI., 1982a). This in­ The mechanism by which auranofin acts to de­ hibition was most notable in cells derived from crease lysosomal enzyme release is unclear. As aur­ patients with rheumatoid arthritis. In some cases, anofin has been shown to inhibit cellular mem­ a stimulatory effect on the 'respiratory burst' (see brane transport mechanisms by its inhibition of 3H_ section 1.3.1) was observed in these mononuclear thymidine transport through lymphocyte cell cells when exposed to lower concentrations of aur­ membrane (Finkelstein et aI., 1977a), it may act at anofin (0.25 to 1.01Lg gold/ml) [Davis et aI., 1982a]. a cellular level to block lysosomal enzyme release In a placebo-controlled trial (Coughlan et aI., (Finkelstein et aI., 1982a). Additionally, auranofin 1983) IgG and IgM-rheumatoid factor production has been shown to be associated with increases in were decreased 85 and 81 %, respectively, in mon­ intracellular cyclic AMP concentrations (Schein­ ocytes from patients with rheumatoid arthritis berg et aI., 1981) which are in tum known to cause treated with auranofin 3mg twice daily for 4 decreased lysosomal enzyme release from poly­ months. An 84% depression of lymphocyte con­ morphonuclear cells (Zurier et aI., 1974). Sodium canavalin A transformation was also noted; how- Auranofin: A Preliminary Review 389

Table III. Comparative effects of auranofin (AF) and sodium aurothiomalate (ATM) on human mononuclear leucocyte function in vitro (adapted from Walz et aI., 1982a)

Reference Function Effect Gold concentrations ("g/ml)

AF ATM AF ATM

Davis et al. (1982a) Mononuclear phagocyte 1.5-2.5 1-100 superoxide production 0.25-1.0

Finkelstein et al. (1982b) Lymphocyte ADCC 1.0-2.0 2-20.0

Harris et al. (1983) Natural killer cell activity 0.25-0.50 10 > 2.58 > 10b

Lorber et al. (1981) Lymphocyte mitogen stimulation + (80%) + (30%) _c _c

Russell et al. (1982) Monocyte ADCC 1.5 Not specified Lymphocyte ADCC _c 0.25-1.0 Not specified 2.5

Salmeron and Lymphocyte nitrogen stimulation + (99% +) + (up to 1.45-14.5 2.5-25 Lipsky (1983) 26%)

Scheinberg et al. (1981) Monocyte chemotaxis + (92%) +(46%) 10"g Au d 10"g Aud a Inhibition occurs only in absence of macrophages. b Inhibition occurs in presence or absence of macrophages. c Mononuclear cells tested in vitro following removal from patients after AF 6mg daily for 20 weeks (mean serum gold concentration 0.3-1.0 "g/ml) or ATM 50 or 75mg weekly x 20 weeks (mean serum gold concentration> 3 "g/ml, 7 days post-administration). d Concentration of AF or ATM gold/Boyden chamber. Abbreviations: ADCC = antibody-dependent cellular cytotoxicity; + = decrease; t = increase; - = no change.

ever, IgM production and monocyte phagocytosis ml and aurothioglucose 3 mgfml (Jessop et aI., of Candida albicans were not significantly affected 1982). by the treatment. In monocytes derived from healthy volunteers 1.4 In Vitro Effects on DNA, RNA, and and patients with rheumatoid arthritis, concentra­ Protein Synthesis tions of auranofin ranging from 0.1 to I O.O~g gold/ ml markedly reduced chemotactic activity, with In vitro, auranofin 0.5 to 1.0~g gold/ml selec­ I O.O~g gold/ml causing a 92% reduction in peri­ tively decreased DNA, RNA, and protein synthesis pheral blood monocyte chemotaxis (Kleine, 1983; in human cell cultures of HeLa (epitheliod) carci­ Scheinberg et aI., 1981). Significant in vitro inhi­ noma, RAJI lymphoma, and Epstein-Barr virus­ bition of human monocyte chemotaxis by auran­ transformed human lymphocytes. Within the ini­ ofin was also demonstrated by Kleine et ai. (1981) tial 2 hours of incubation with auranofin, DNA and Scheinberg et ai. (1979). Auranofin 0.12S~g synthesis was inhibited by 73 to 83% in Epstein­ gold/ml reduced by up to SO% the capacity of hu­ Barr virus-transformed cells and by 90% in RAJI man monocytes to undergo antibody-dependent cells in contact with I~g gold/ml. Significant in­ cellular cytotoxicity in response to antibody-coated hibition of RNA and protein synthesis occurred at red blood cells (Kleine, 1983; Russell et aI., 1982). 24 hours in Epstein-Barr virus-transformed cells Synovial macrophage phagocytic activity in and at 2 hours in RAJI cells, but did not persist synovia removed from patients with rheumatoid (Simon et aI., 1979a,b). In HeLa cells, however, arthritis was suppressed 26% by auranofin 10 mg/ auranofin O.S and 1.0~g gold/ml persistently inhib- Auranofin: A Preliminary Review 390

ited incorporation of 3H-thymidine into DNA by gation of platelets is not known; however, the abil­ 70 and 90%, respectively. As in other cell prepar­ ity of auranofin to increase platelet cyclic AMP ations, the effect on RNA and protein synthesis concentrations (similar to those seen in leucocytes was less marked than that on synthesis of DNA. following auranofin) [Scheinberg et aI., 1981], or Membrane transport of 3H-2-deoxy-D-glucose was to inhibit prostaglandin function (Lamprecht et aI., not blocked by auranofin, suggesting that de­ 1981) [section 1.5.2], may contribute to this effect. creased membrane transport was not a primary mechanism of action in the inhibition of DNA syn­ 1.5.2 In Vitro Effect on Prostaglandin Activity thesis (Simon et aI., 1979a, b). Auranofin IOJLg gold/ml suppressed the stimu­ Significant morphological changes (rounding, latory action of prostaglandin E, on ovarian cyclic pitting, tearing, and 'blebbing' of the cell mem­ AMP formation by 50 to 70% in prepubertal rat brane) occurred in HeLa cells following incubation ovaries (Lamprecht et aI., 1981). This inhibitory with auranofin 0.5 to 1.0JLg gold/ml for 6 hours effect was blocked by dithiothreitol, indicating that (Simon et aI., I 979a,b). The cause of these changes auranofin exerted its action through interference is unclear. However, auranofin induces a dose-re­ with protein sulfhydryl groups. Although it is lated decline in oxygen uptake and viability in HeLa known that gold compounds may interfere (how­ cells, which parallel these morphological changes. ever weakly) with prostaglandin biosynthesis, these The changes are suggestive of cell cycle sensitivity results appear to indicate that auranofin is capable to auranofin or membrane damage and cell death of blocking plasma membrane prostaglandin re­ (Lorber, 1982). Similar morphological changes oc­ ceptor-mediator events. cur in peripheral lymphocytes of patients with rheumatoid arthritis treated with auranofin, but not 1.5.3 Antitumour Activity In Vitro in untreated patients or patients administered sod­ Due to the impressive inhibitory effects of aur­ ium aurothiomalate (Lorber et aI., 1979a). anofin on essential cellular functions (DNA, RNA, Structural analogues of auranofin (with methyl, and protein synthesis, respiration, etc.) in cultured isopropyl, or phenyl group exchanges in the tri­ human cancer cells (HeLa, KB, RAJI) and patient ethyl phosphine moiety of the molecule) in concen­ mitogen and skin test responses (sections 1.2.2, 1.3 trations of 0.25 to 1.0JLg gold/ml have also been and 1.4), the antitumour activity of auranofin in shown to decrease 3H-thymidine incorporation into mice inoculated with lymphocytic leukaemia P388 the DNA of HeLa cells, while inducing morpho­ was studied (Simon et aI., 1981). Auranofin 3 to logical changes identical to those caused by the 7.5 mg/kg inhibited the growth of this tumour in parent compound (Simon et aI., 1983). mice. and in some cases was more active than 5- fluorouracil. Treatment of leukaemic mice with 1.5 Other Effects auranofin was also associated with significant pro­ longation of the median survival time. Since aur­ 1.5.1 In Vitro Effect on Platelet Aggregation anofin was active in this tumour model and in in In platelet-rich plasma derived from human vitro propagated human cancers [B16 melanoma; blood, auranofin 10JLg gold/ml was found to be a HT-1080 human sarcoma; HT-29 human colon potent inhibitor of platelet aggregation induced by carcinoma; chago, human bronchogenic adenocar­ ADP, adrenaline, or collagen (Nathan et aI., 1982). cinoma (Crooke and Mirabelli, 1983; Mirabelli and Inhibition was most evident during the second Crooke. 1983)1 and is well tolerated, further in­ phase of aggregation, and was directly proportional vestigational studies of its anti tumour efficacy may to drug preincubation time. In parallel studies, be indicated. aurothioglucose caused less inhibition of collagen­ and adrenaline-induced platelet aggregation. The 1.5.4 Effects on Copper and Zinc Metabolism mechanism by which auranofin decreases aggre- Gold compounds have been shown to exert ef- Auranofin: A Preliminary Review 391

fects on copper (Lewis et aI., 1980; Mason et aI., tion hold any significance for the patient with 1980) and zinc (Mason et aI., 1980; Ward et aI., rheumatoid arthritis remains somewhat specula­ 1981) homeostasis. Auranofin decreased plasma tive, and will likely only be clearly understood when copper concentrations in adjuvant arthritic rats the aetiology of rheumatoid arthritis is known. coincident with reducing inflammation (Lewis et The formation of immune complexes and rheu­ aI., 1980), and a positive correlation (p < 0.01) was matoid factors are thought to be a stimulus to joint found between reduction in erythrocyte sedimen­ destruction in rheumatoid arthritis (Bonta et aI., tation rate and decrease in plasma copper concen­ 1980), and some of the activity of auranofin on trations in patients with rheumatoid arthritis re­ immune system function may be related to its in­ sponding to auranofin or sodium aurothiomalate hibitory effects on protein formation (sections 1.3 (Ward et aI., 1981, 1983a). Among the 12 patients and 1.4). In patients with rheumatoid arthritis re­ who responded to auranofin or sodium aurothio­ sponding to gold treatment, increases in albumin malate and had low initial plasma zinc concentra­ concentrations are often accompanied by decreases tions « 10.0 J.Lmol/L), 10 demonstrated increases in serum immunoglobulin concentrations, suggest­ in zinc concentrations which existed in significant ing that gold compounds do not act by a general inverse correlation with the decreases in plasma suppression of protein synthesis (Harth, 1979). It copper concentrations. Although the significance is unclear, however, whether auranofin decreases of these data is not known, they suggest that an antibody and serum immunoglobulin concentra­ interrelationship between copper and zinc plasma tions by a direct and selective interference with concentrations exists in patients with rheumatoid protein synthesis, or indirectly via an effect on the arthritis responding to auranofin and other gold triggering aetiological factor(s) of the disease (Fin­ compounds. kelstein et aI., 1976; Harth, 1979). Inhibition of synovial cell proliferation and collagen synthesis 1.6 Mechanism of Action may also contribute to the beneficial effects of gold compounds in rheumatoid arthritis (Bonta et aI., There is a wealth of evidence which strongly 1980). suggests that immunological processes playa ma­ Inhibition of lysosomal enzyme synthesis or ac­ jor role in the chronic synovitis which is charac­ tivity may be responsible for some of the activity teristic of rheumatoid arthritis (Gilliland and Man­ of gold compounds in rheumatoid arthritis (Bonta nick, 1980; Lipsky and Ziff, 1977; Salmeron and et aI., 1980; Oi Martino and Walz, 1977; Finkel­ Lipsky, 1982). It would seem reasonable to suggest stein et aI., 1982a; Lewis et aI., 1980; Menninger that the effectiveness of auranofin may be due to and Burkhardt, 1983a). Lysosomes are the princi­ its ability to modify various immunological pro­ pal site of gold localisation and concentration in cesses. Most in vitro and in vivo studies have dem­ tissues (Shaw, 1980). The lysosomal bodies con­ onstrated the immunosuppressant properties of taining soluble gold compounds have a particular auranofin, but a few have reported immunological morphological pattern, and have been termed 'au­ enhancement (sections 1.2 through 1.3.2; tables I, rosomes' (Ghadially, 1979). Neutrophils and phag­ 11 and III). The effects of aura no fin on the immune ocytic synovial cells are known to secrete lyso­ system may be condition-dependent, with somal enzymes into joint spaces during immune immunostimulation or inhibition depending upon complex phagocytosis and following phagocytic cell prevailing conditions. Thus, auranofin has been contact with antigen-antibody complexes, resulting termed an 'immunoregulating' or an 'immunom­ in inflammation and tissue injury (Finkelstein et odulating' agent (Bernhard, 1982a; Kaplan, 1983; al.. I 982a). In cells removed from laboratory ani­ Lewis et aI., 1980; Lorber et aI., 1981, 1982; Walz mals and man, auranofin has been shown to be a et aI., 1981). However, despite such findings, potent inhibitor of i3-glucuronidase, lysozyme, and whether the effects of auranofin on immune func- acid phosphatase release, and of cathepsin-B, ac- Auranofin: A Preliminary Review 392

tivity (Bonta et al., 1980; Di Martino and Walz, effects on copper homeostasis (Mason et aI., 1980), 1977; Di Martino et al., 1974; Finkelstein et al., despite having similar efficacy in rheumatic dis­ 1982a; Ladizesky et al., 1979) [section 1.3.1]. Since eases. It is not yet clear whether an elevated or a the synovial fluid from patients with rheumatoid decreased (from baseline values) serum copper arthritis has been shown to be rich in these en­ concentration is most consistent with optimal anti­ zymes, any direct or indirect pharmacological in­ rheumatic activity (Lewis et aI., 1980). terference with these substances may be of value in modulating the inflammatory response and in­ 1.7 Toxicology Studies hibiting the destruction of cartilage and bone (Bonta et al., 1980; Finkelstein et al., 1982a). 1.7.1 Acute Toxicity Gold compounds are known to inhibit prosta­ The acute toxicity of auranofin has been eval­ glandin synthesis, and this has been suggested as a uated in Charworth Farm Swiss mice and in Charles possible mechanism of action in rheumatoid arth­ River rats, in which the median lethal oral doses ritis (Bonta et al., 1980; Gottlieb, 1977; Hanna et were 310 and 265 mg/kg, respectively (Saunders, al., 1983; Lamprecht et al., 1981; Lewis et al., 1980). 1983). The inhibition induced by gold compounds is weak (Bonta et aI., 1980); however, auranofin has been 1.7.2 Subacute and Chronic Toxicity demonstrated to inhibit prostaglandin activity, and In a I-year study, auranofin 1.0, 3.5, and 1O.Omg not synthesis (Lamprecht et aI., 1981) [section gold/kg daily produced dose-related changes in rats, \.5.2]. Although blockade of prostaglandin activity including weight loss, increased salivation, soft occurs in vitro, it is not known whether it occurs faeces, anaemia and leucocytosis (Payne and Ar­ to any significant degree in patients with rheu­ ena, 1978a). The haematological abnormalities were matoid arthritis treated with auranofin. believed to be secondary to auranofin-induced gas­ Other proposed mechanisms of action for aur­ trointestinal lesions, rather than direct effects on anofin and other gold compounds have been in­ the bone marrow. Drug-related lesions in these rats activation of the first component of complement included renal tubular cell karyomegaly, cytome­ (Gottlieb, 1977; Harth, 1979; O'Duffy, 1979), an galy, adenomas, gastric erosions and ileocoecocolic anti-infective action (Bonta et aI., 1980; O'Duffy, ulcers (Payne and Arena, 1978a; Payne and Saun­ 1979), and a lowering of serum copper concentra­ ders, 1978). Renal tubular cell karyomegaly does tions (Lewis and Walz, 1982; Lewis et aI., 1980; not increase mortality; however, continued dosing Mason et aI., 1980; Ward et aI., 1981, 1983a). for a year or more has resulted in neoplasia of the However, as there is no convincing evidence that tubular cells. Although drug-related lesions in la­ a bacterium or virus is the initiating agent in the boratory animals are common following long term immunological and inflammatory processes which heavy metal exposure, ileocoecocolic ulcers have constitute rheumatoid arthritis, the suggestion of not been reported with sodium aurothiomalate an anti-infective mechanism for gold compounds (Payne, 1982). is one which is highly conjectural (Gilliland and Dogs administered auranofin 1. 8 to 18mg gold/ Mannick, 1980). Auranofin has been shown to de­ kg/day for 3 months or 0.6 to 6.0 mg/kg/day for I crease serum copper concentrations in adjuvant year exhibited dose-related emesis, diarrhoea, and arthritic rats and in patients with rheumatoid arth­ decreased food consumption and bodyweight ritis coincident with disease improvement (section (Payne and Arena, 1978b). The higher dose groups 1.5.4). and it has been suggested that displacement also had decreased haemoglobin and packed red of this trace element from abnormal binding sites blood cell volumes. In the dogs treated for I year, may favourably modify the course of rheumatoid decreases in total serum protein and albumin were arthritis (Lewis et aI., 1980; Ward et aI., 1983a). noted. as well as hyperplasia of thyroid tissues. A However. different gold compounds exert varying subclinical anaemia with normal bone marrow re- Auranofin: A Preliminary Review 393

sponse was apparent in middle and high dose macokinetic properties of auranofin and other gold groups (Payne and Arena, 1978b). antirheumatic agents are listed in table IV.

1.7.3 Effects on Reproduction 2.1 Absorption Oedema was the only major defect noted in fe­ tal offspring from pregnant rats administered aur­ Auranofin contains aurous gold, which is sta­ anofin 0.1 to 23.2mg gold/kg/day during days 6 bilised by dual sulphur and phosphorus ligands. The through IS of pregnancy (Szabo et aI., 1978b). It molecule is therefore hydrophobic rather than hy­ was unclear whether the oedema was due to a di­ drophilic, and carries no ionic charge. These prop­ rect effect on the embryo or was secondary to ma­ erties facilitate the absorption of the compound ternal auranofin toxicity. Significant decreases in fol1owing oral administration (Lorber, 1982; Stote maternal food consumption and bodyweights, and et aI., 1983; Sutton et aI., 1983). in fetal bodyweights were also noted. Maternal Auranofin is rapidly but incompletely absorbed mortality was 17% in the highest dose group. after oral administration. The use of intravenous Auranofin induced abortion, increased resorp­ and oral 195Au-labelled auranofin in dogs has sug­ tion, decreased litter size, and fetal weight when gested that approximately 25% of an oral dose is given in a dosage of 0.1 to 22.6 mg/kg/day to preg­ absorbed (Gottlieb, 1982, 1983). Model-dependent nant rabbits (Szabo et aI., 1978a). Dose-related de­ absorption estimates in man have averaged ap­ creases in maternal food consumption occurred, proximately 24% (range 15 to 38%) of the oral dose and the higher dosages of aura no fin (9.3 and 22.6mg administered (Blocka et aI., 1981, 1982; Furst et gold/kg/day) resulted in maternal death. The most aI., 1982). prominent and constant fetal abnormalities asso­ Weisman et al. (1980) assessed the movement ciated with auranofin were abdominal defects such of auranofin in the intestinal tract of healthy as gastroschisis and umbilical hernia. Anomalies of volunteers and rheumatoid arthritis patients with the brain, heart, lung and skeleton were seen less a triple lumen intestinal infusion apparatus in con­ frequently. junction with a non-absorbable radio-label1ed marker dilution technique. It was unclear whether transmucosal absorption occurred. The findings 2. Pharmacokinetics of Auranofin were most consistent with 'loose' reversible ad­ sorption of auranofin onto the enteric cel1 surface, The major distinctive pharmacokinetic prop­ with subsequent elution into intestinal fluid. The erty of auranofin is its absorption after oral admin­ precise location and mechanism of auranofin ab­ istration. Numerous single-dose and/or long term sorption remains unknown (Bernhard, 1982a). studies have been conducted in laboratory ani­ mals, human volunteers and patients with rheu­ 2.2 Plasma Concentrations matoid arthritis to determine the distribution and elimination characteristics of this gold compound. Gold concentrations following single-dose and Serum, plasma and whole blood gold concen­ maintenance auranofin administration have been trations have been determined by radioisotopic and determined using radioisotopic techniques (Blocka atomic absorption spectrophotometric techniques, et aI., 1980, 1981, 1982; Furst et aI., 1982) and the while the more sensitive carbon rod atomisation atomic absorption spectrophotometric methods procedure has been used in both in vitro and in described by Lorber et al. (1968). The serum of l'il'O erythrocyte and lymphocyte binding studies. healthy subjects not treated with gold-containing Data on the effects of age, renal insufficiency compounds contains less than 0.05 ng/ml of gold and hepatic dysfunction on the pharmacokinetics (Gottlieb, 1982, 1983). Optimally, pharmacokin­ of auranofin are incomplete or lacking. Some phar- etic studies of auranofin should include assessment Auranofin: A Preliminary Review 394

Table IV. Some important pharmacokinetic properties of auranofin and other widely used chrysotherapeutic agents in man (data from Australian National Drug Information Service. 1982: Bandilla et aI., 1982; Blocka, 1983; Blocka et aI., 1980, 1982; Blocka and Landaw, 1983; Furst et aI., 1982; Gerber et al., 1972; 1974; Goobar and Horton, 1983; Gottlieb, 1980, 1982, 1983; Gottlieb et aI., 1974; Herrlinger, 1983; Herrlinger et al., 1982; Homma et al., 1982; Jessop and Johns, 1973; Lorber, 1980; Lorber et al., 1973; Mascarenhas et al. 1972; Pedersen and Graabaek, 1980; Rubenstein and Dietz, 1973; Smith et aI., 1973; Stote et aI., 1983; Van de Stadt and Abbo-Tilstra, 1980)

Pharmacokinetic variable Auranofin Sodium Aurothioglucose aurothiomalate

Time to reach peak blood/serum concentrations of gold (hours) 1-1.5 1-6 4-13

Time to reach steady-state serum concentrations of gold (weeks) 8-12 6-12 6-15

Range of usual steady-state serum concentrations of gold (ltg/ml) 0.3-1.0 1-5 1-5

Apparent volume of distribution plasma compartment (L) 4.95-9.34"

Protein binding (%) 60 '" 95 85-95

Blood cell distribution (%) 40 0-37 10-35b

Synovial fluid/serum or whole blood gold ratio 1 : 1.7 1 : 1.8

Route of excretion (% of total) renal '" 12 60-90 60-90 enteric '" 88 10-40 10-40

Urinary clearance (ml/min) 0.075-0.305C 0.1-0.2 0.1-0.2

Enteric clearance (ml/min) 0.035-0.551c

Half-life (days) initial serum O.17d 4.5-7.5d.e terminal serum 17d-25.5" 10-35d '" 25" total body terminal 57.6d -80.9" 30-168e Up to 168e a Initial apparent volume of distribution calculated from serum clearances; not corrected for protein binding. b This range of blood cell distribution only found in up to 45% of patients tested. c Calculated on basis of 70kg bodyweight. d Following single dose. e Following long term, multiple-dose therapy.

of both blood and serum gold concentrations (Haf­ after a 6mg dose of radio-labelled auranofin was strom, 1983; Walz et aI., 1979b). During auranofin administered to patients who had been treated with treatment, gold concentrations in plasma or serum auranofin 3mg twice daily for 6 months (Blocka et have been virtually identical (Gobblieb and Gray, aI., 1982). 1980); whole blood gold concentrations may be Steady-state serum or whole blood gold concen­ higher or lower depending upon the patient's hae­ trations are achieved after 8 to 12 weeks of con­ matocrit. tinuous auranofin therapy (Bandilla et aI., 1982; In patients with rheumatoid arthritis, mean peak Calin et aI., 1982; Champion et aI., 1982; Furst et plasma concentrations of 0.066 to 0.23p,g 195 Au/ml aI., 1982; Goobar and Horton, 1983; Homma et aI., were attained 102 to 120 minutes following a single 1982). Plasma gold concentrations following at least 6mg dose of radio labelled auranofin (Blocka et aI., 12 weeks of auranofin 2 to 9mg daily were 0.20 to 1980, 1982), whereas a mean peak plasma concen­ 1.0 p,g/ml, respectively (Bernhard, 1982a; Cham­ tration of O,085p,g '95Au/ml occurred 72 minutes pion et aI., 1981), Once plasma gold concentrations Auranofin: A Preliminary Review 395

have reached plateau levels, little individual vari­ 2.3 Distribution ation occurs if maintenance therapy with aurano­ fin is continued (Bandilla et al., 1982; Champion In laboratory animals and man the pattern of et al., 1981; Gottlieb, 1982). distribution of auranofin gold differs from that of In children (7 to II years old) with juvenile parenterally administered compounds. However, rheumatoid arthritis administered an equivalent the clinical significance of this is unclear, since it dose (0.1 to 0.2 mg/kg/day), gold concentrations is not known whether it is the free gold, the frac­ were somewhat lower than those seen in adults tion bound to albumin, or that associated with cells (Giannini et al., 1983b). There is a significant cor­ which is pharmacologically active (Blocka, 1983; relation between the daily dosage of auranofin and Hafstrom, 1983) [see introduction, section I]. the resultant plasma and/or whole blood concen­ The intracellular distribution of auranofin has trations in adults (Champion et al., 1981, 1982; not been studied in specific detail, and there are Finkelstein et al., 1980) [fig. 2] and children (Gian­ no reports of its apparent volume of distribution. nini et al., 1983a), with an increase of approxi­ mately 0.1 ~g/ml in mean serum gold concentra­ 2.3.1 Extracellular Distribution tion for every I mg increase in daily dosage (Champion et al., 1982). Unbound Serum Gold In most studies there appeared to be no corre­ U sing an analytical procedure enabling quanti­ lation between plasma or whole blood gold con­ tation of gold at concentrations as low as 0.005 /Lg/ centrations and therapeutic efficacy (Berglo[ et al., ml, Lorber et al. (1983a) determined that unbound 1978; Caruso et al., 1981; Champion et al., 1981; serum gold represented 0.6% of the total serum gold Giannini et al., 1983a; Schorn, 1982) or the inci­ concentration (mean 0.81 /Lgfml) after auranofin dence of toxicity (Davis et al., 1981; Hafstrom, administration. In patients receiving maintenance 1983) associated with auranofin therapy. It is un­ intramuscular sodium aurothiomalate, unbound clear whether the efficacy of auranofin correlates serum gold concentrations represented only 0.26 with the concentration of blood cell-associated gold and 0.20% of the pre- and post-administration total (Walz et al., 1981). serum gold levels (mean values 0.245 and 0.520 /Lg/ml), respectively. As recent evidence (Lorber et al., 1983a) suggests that the unbound portion of the total serum gold concentration is active in sup­ E-.. pressing several human immune cell functions, the 0) ..:!o lesser binding of auranofin compared with that of § 1.0 sodium aurothiomalate may in part explain the 0 n = 40 ~ 0.9 0 differences in effects of these drugs on immune cell c: 0.8 ~ 0.7 function (see section I). n = 139 § 0.6 • ~ 0.5 Plasma Protein Binding g, 0.4 "0 0.3 Distribution to plasma proteins accounted for n = 134 g 0.2 59.9% of the mean whole blood concentration of iIi 0.1 n = 49 • auranofin gold (1.25 /Lg/ml) in patients with rheu­ 2 3 4 5 6 matoid arthritis who had undergone at least 3 Duration of administration (months) months of auranofin therapy (Herrlinger et al., 1982). Of the amount of auranofin gold bound to Fig. 2. Average whole blood gold concentrations following daily doses of auranofin 1mg (...... ), 2mg (0---0), 6mg plasma proteins, 82% was bound to albumin and (___ ..... ) or 9mg (0---0) in patients with rheumatoid arthritis 18% to immune globulins. On separation of the (after Heuer and MorriS, 1983). immune globulin molecules, 4.8% was bound to iX,- Auranofin: A Preliminary Review 396

globulin, 6.9% to

70 70 [Tausch et aI., 1983]. In erythrocytes of patients treated with auranofin (section 2.3.1), 37% and 3% of the mean whole blood concentration of auran­ 60 60 ofin gold was distributed in the erythrocyte hae­ molysate and cell membranes, respectively (Herr­ 50 50 linger, 1983; Herrlinger et aI., 1982). Erythrocyte haemolysate gold concentrations following treat­

40 40 ment with auranofin are higher in patients who smoke, although there is no correlation between the '6 0; ..:; number of cigarettes smoked and haemolysate gold c 30 30 0 concentration, as with sodium aurothiomalate .~ (Lewis et aI., 1983). c Q) 20 20 By use of cell fractionation procedures and car­ "c 0 bon rod atomisation analysis, Lorber et al. (1979b) "0" (5 demonstrated that for each gold compound tested

much higher (4 to 7 JIg/ml) after treatment with 2.3.4 Gold Retention sodium aurothiomalate. Gold has been detected in The amount of gold retained during chryso­ chromatin from lymphocytes of patients treated therapy can be influenced by a number of factors: with auranofin or sodium aurothiomalate (Tausche the dose of the agent, frequency of dosage, route et aI., 1983). The clinical significance of these find­ of administration, the compound given, and the ings is unknown. patient's own rate of excretion (Gottlieb and Gray, Auranofin gold is bound to platelets in vitro and 1980). Retention can be indirectly estimated using in vivo (Herrlinger et aI., 1982) to an extent similar radioisotopic balance studies. Direct quantitation to that following treatment with sodium aurothio­ of gold content in tissues or organs can be per­ malate (Lorber et aI., 1979b). The effect of aur­ formed from samples taken by biopsy, at surgery, anofin on platelet aggregation is discussed in sec­ or at postmortem examination, and by use of a tion 1.5.1. whole body radiation counting chamber following radioisotope administration. 2.3.3 Tissue Distribution Direct and indirect studies 10 days following Little is known of the organ and tissue distri­ ingestion of a single 6mg dose of 195 Au-labelled bution of gold associated with auranofin therapy auranofin revealed that total body retention ac­ (Gottlieb and Gray, 1980). Because only small counted for 15%, and cumulative faecal and urin­ amounts of gold are retained during long term ary excretion for 79.7%, of the total reactivity therapy with auranofin (section 2.3.4), it can be ex­ (Blocka et aI., 1980). 100 days following adminis­ pected that tissue gold concentrations will be less tration of the single dose, less than 5% of the total than those associated with parenteral treatment reactivity was retained. In contrast, greater than (Gottlieb and Gray, 1980). Walz et al. (l979b) 50% retention occurred 100 days after a single 50mg compared the gold content of rat liver, kidney, and dose of 195Au-Iabelled sodium aurothiomalate spleen following I year's administration of aur­ (Blocka et aI., 1980). anofin 6.7mg gold/kg/day orally or sodium auro­ It has been estimated that sodium aurothio­ thiomalate 6.06mg gold/kg/day intramuscularly. malate 50mg weekly for 20 weeks will result in total Despite nearly equivalent blood gold concentra­ body retention of 300mg of elemental gold, whereas tions, organ gold concentrations following auran­ auranofin 6mg daily will result in only 59mg of ofin were only 1.4 to 3.0% of those found in the elemental gold being retained over the same pe­ sodium aurothiomalate-treated rats. riod. Other estimates of gold retention following Punch biopsies performed on the skin of 4 auranofin 6mg daily for 6 months have been sub­ patients with rheumatoid arthritis treated with aur­ stantially lower (5 to 17mg) [Furst, 1983]. Auran­ anofin (total dose 945 to 3600mg over 2.3 to 2.5 ofin 2mg daily for 20 weeks was estimated to result years) revealed a detectable gold concentration (1 in no retention (Gottlieb, 1979a, 1982, 1983). Jig/g) only in the skin of the patient with the high­ est cumulative dose (Gottlieb, 1982, 1983). Similar 2.4 Excretion total dosages of parenteral gold compounds have resulted in skin gold concentrations of 2.6 to 26.5 In the first 10 days after administration of a JIg/g, with concentrations correlating with increas­ single 6mg dose of 195Au-Iabelled auranofin to 6 ing dosages (Gottlieb, 1981, 1982). patients with rheumatoid arthritis, urinary and fae­ Hair and nails have only a small affinity for gold, cal excretion accounted for 3.7 to 5% and 70 to whether administered orally or by injection (Gott­ 76% of the total radioactivity, respectively (Blocka lieb, 1982). In these tissues, gold concentrations et aI., 1980, 1982; Furst et aI., 1982). Six months following long term auranofin therapy have been after the single dose, cumulative urinary and faecal comparable with those in patients receiving long excretion accounted for 13.5 to 15% and 88 to 89%, term parenteral gold treatment (Gottlieb, 1981). respectively, of the total radioactivity (B1ocka et > Table V, Summary of open studies of auranofin (AF) in the treatment of active rheumatoid arthritis s:: I""1 ::) 0 Reference Number of Dose and dosage Antirheumatic efficacyC :=-. patientsb schedule of auranofin ? activity duration time to articular ESR grip no, of rheumatoid [study > index morning onset of index strength tender/ factor ." duration, "1 stiffness fatigue swollen ~ months] S' joints S' I" Bandilla et al. (1982, 126 [~12] 6mg daily ++ ++ 0 ++ ++ 0 +/+ ~ :;.;l 1983a,b) (or 3mg bid) r1> <: (j)' Berglof et al. (1978) 8 [3] 3mg bid ++ + ++ ++/++ ++ $! Caruso et al. (1981, 22 [18] 3mg bid ++ ++ ++ ++ ++ ++ ++/++ 1983)

Ciompi et al. (1983) 7 [12] 3mg bid + ++ 0 ++ + + Ghozlan et al. (1983) 87 [3-12] 3mg bid ++ ++ ++ ++ ++ ++ ++/++ Goobar and Horton 10 [12] 3mg bid x 12-16 weeks, ++ ++ ++ ++ ++ ++/++ + (1983) then 4 or 7mg daily, depending upon response to treatment

Hafstrom (1983) 17 [12] 6mg daily or 3mg bid for ++ ++ ++ 0 6 months, then 3mg daily to a random group of responders

Homma et ai, (1982) 47 [6] 3mg bid ('mostly') ++ ++ ++ ++ ++ ++/++ Hunt and Holt (1981, 14 (12] 4mg daily, increased to + + -/+ + 1983) 6mg daily after 4 months, and 8mg daily after 4 additional months, depending on clinical and/or laboratory response

Lorber (1980) 14 [12] 3mg bid ++ 0 + ++/++ 0

Meyers (1979)" 12 [3] 4mg daily + + +/+ 10 [3] 6mg daily + + +/+

w 'C> 00 Auranofin: A Preliminary Review 399

cE a\.,aI., 1980, 1982; Furst et aI., 1982). Long term treat­ CD E ment with auranofin (3mg twice daily for 21 months) resulted in a steady-state rate of urinary + a.~ 00+ .5 gold excretion of 250 to 400 /Lgjday (Caruso et aI., I 1981), and urinary gold excretion has correlated + + B highly (r = 0.739) with blood gold concentration + + + ~ + + --++ c: +" :t+ +" .2' following auranofin administration (Finkelstein et + "II + Ul ...'"~ aI., 1980; Gottlieb, 1979b; Homma et aI., 1982)1982). . ! I!! The major portion of faecal excretion of a single CIC) c: dose of auranofin occurs within the first 4 days after + + + 0 ! administration in man (Blocka et aI., 1980). On the Ul '"9l basis of human studies (Gottlieb and Gray, 1980), B and those in rats (lntoccia et aI., 1982), the high + + + 0 + ~ faecal gold content associated with auranofin 51 .5 administration is principally due to incomplete ab­ g sorption, although mucosal adsorption with sub­ o + + sequent sloughing into the lumen of the gut and + + v .s secretion of gold through the intestinal wall and via cE B the biliary tract are probably contributory. The lat­ !E c: ter possibilities are supported by the finding in man S2. .2' Ul that the excretion of auranofin gold is delayed sev­ + '"11II + eral days when compared with simultaneously ad­ + ministered stool markers (Blocka et aI., 1981). + + + 1 Renal clearance of auranofin has varied be­ + + + 8. I!! tween 0.064 and 0.26 ml/h/kg and enteric clear­ g ance between 0.03 and 0.47 ml/h/kg (Blocka et aI., 1982; Furst et a\.,aI., 1982). + + j The initial serum half-life of auranofin in 6 ·c'2 x ~ CIC) patients with rheumatoid arthritis administered a ",CD ·iii'iii ='C is single 6mg radio labelled dose was about 4 hours ~ ~ ~.~ c: ~ o c: (Blocka and Landaw, 1983), whereas the terminal ~ x ~ ~ i::sq:: ~ plasma half-life of a single 6mg radiolabelled dose x~l5-g"'. ~ 'iii '2 'C-,=III was 17 and 25.5 days before and after 6 months' .?:'e»-UJ ~ .~ ~1S treatment with auranofin 6mg daily. In the same ~ ~ ~~~~:a III c: C) C) C)c:c~~ u • . == 'E patients, mean terminal total body half-life was 57.6 ~ ~ ~~~MO ",CD CD '2 CD E and 81 days before and after long term dosing 0-,= CD E -c: 0 > (Blocka et aI.,a\., 1982). Similar values were recorded N :€ CL ..- - ~ £ is S~~ by other investigators (BerglOf et a\.,aI., 1978; Blocka 1:; -8 .- !.~~§~ III :;, II et a\.,aI., 1980, 1981; Gottlieb and Gray, 1980). NM M...... It) coIi' '5_ igg+ .£l .- +.: III Ul c: c: C II) .- CD E 3. Therapeutic Trials ~ M 'C+,CD '" CIO CD III > -:; '"~ 'CO; 5~[ ~ ~ 5 S; a.°E Auranofin has been studied in open trials and II) en .v ..... e i .- ",..0 0 ca !:.. c: ";;" '0 E c: in a limited number of comparative trials in CD E ~:E .a ::I II :::I 0 (/) c: OOZo patients with active rheumatoid arthritis. The need C) -'= .- c: ~ ~ ~ ~ asIII .c..0 u0 for long term study of a disease-modifying drug in Auranofin: A Preliminary Review 400

rheumatoid arthritis was recognised in a minority tomical stage II) of about 6 years' duration. of studies in which treatment continued for at least Although most studies have been conducted for 2 years. Most studies, however, have been con­ around 12 months or more, others have been too ducted for 12 months or less. brief to provide useful data on the efficacy of a The criteria for assessing disease activity and potentially disease-modifying antirheumatic agent. therapeutic efficacy have usually included articular In most instances, the study protocol allowed index, walk time, grip strength, duration of morn­ the concomitant administration of non-steroidal ing stiffness, pain, physical wellbeing, global as­ anti-inflammatory and/or analgesic drugs with aur­ sessment by patient and/or physician and altera­ anofin, and in several studies patients who were tions in erythrocyte sedimentation rate, C-reactive receiving maintenance corticosteroid treatment protein, rheumatoid factor titre, and immunoglob­ participated in the study. Patients who had re­ ulin concentrations. Auranofin in fixed dosages has ceived previous courses of remission-inducing been compared with placebo (section 3.1.3), sod­ agents (parenteral gold compounds, chloroquine, ium aurothiomalate (gold sodium thiomalate) [sec­ D-penicillamine and cytotoxic agents) were admit­ tion 3.1.4], D-penicillamine (section 3.1.5), hy­ ted to at least 7 open studies (Bandilla et aI., 1982; droxychloroquine (section 3.1.5) and levamisole Ciompi et aI., 1983; Ghozlan et aI., 1983; Haf­ (section 3.1.5). A preliminary study assessed the strom, 1983; Homma et aI., 1982; Hunt and Holt, value of auranofin in the treatment of juvenile 1983; Noguera et aI., 1983). Although these drugs rheumatoid arthritis (section 3.2). had been withdrawn 3 to 6 months before comm­ encing treatment with auranofin, Bandilla et al. 3.1 Rheumatoid Arthritis (1982) reported detectable serum gold in 17 (23%) of 74 patients at the start of their trial. It is well established that the natural course of Open studies (table V) have suggested that aur­ rheumatoid arthritis is variable and unpredictable anofin is an effective antirheumatic drug, as evi­ and frequently characterised by spontaneous re­ denced by improvement in articular index, activity missions and exacerbations. Also, drug response index, duration of morning stiffness, and erythro­ may be greatly influenced by psychological factors. cyte sedimentation rate, and a decreased require­ Therefore the full clinical evaluation of a new anti­ ment for concomitant antirheumatic drug therapy. rheumatic agent, which is perhaps capable of in­ As with other chrysotherapeutic agents, response ducing remission, requires long term well-designed to auranofin (2 to 6mg daily) is delayed. Changes comparative therapeutic trials in homogeneous in articular index and erythrocyte sedimentation patient groups (Lipsky, 1983). rate have sometimes occurred only after 36 to 48 weeks of treatment (Bandilla et aI., 1982; Noguera 3.1.1 Open Studies et aI., 1983). Although open studies involving small numbers The effect of auranofin on erythrocyte sedimen­ of patients (e.g. BerglOf et aI., 1978; Ciompi et aI., tation rate has been variable, with approximately 1983; Meyers, 1979) can provide little definitive equal numbers of studies reporting either a sig­ data on the therapeutic efficacy and overall toler­ nificant decrease or no change. However, in 2 of ability of a drug used to treat rheumatoid arthritis, the 5 studies reporting no change in erythrocyte long term open trials can provide useful data when sedimentation rate, duration of treatment was only large numbers of patients are involved. 3 months. Rheumatoid factor titres were also in­ A vailable reports of open trials with auranofin consistently influenced by auranofin. Recent stud­ have involved only relatively small numbers of ies (Noguera et aI., 1983; Schorn, 1982) have re­ patients (mostly female, as is typical of a rheu­ ported significant decreases in mean serum IgA, matoid arthritis population) with mild to moder­ IgG, and IgM concentrations following 3 to 12 ately severe disease (average functional and ana- months' treatment with auranofin. Auranofin: A Preliminary Review 401

About half and two-thirds of patients treated by In most of these studies, female patients have Meyers (1979) and Weisman and Hannifin (1979), predominated, and subjects had active rheumatoid respectively, exhibited a favourable clinical re­ arthritis of 3 to 4 years duration. Distribution of sponse to auranofin, but there was no correlation patients according to functional and anatomical between response and steady-state blood gold con­ status was detailed in only I report (Bernhard, centrations (Weisman and Hannifin, 1979). How­ I 982b), where most patients were offunctional class ever, Hafstrom (1983) noted correlations between II, anatomical stage class II. Some studies excluded serum gold concentration and reduction in activity patients who had previously been treated with gold index after 24 weeks' treatment with auranofin, and compounds or other disease-modifying agents between maximum serum gold concentration and (Baldassare et aI., 1980; Calin et aI., 1982; Cham­ reduction in activity index at the end of auranofin pion et aI., 1982, 1983), while including those re­ treatment (up to I year's duration). ceiving systemic or intra-articular corticosteroids. A daily dosage of 6mg, administered as a single Although approximately 26% of the patients stud­ dose or in 2 divided doses, was employed by Haf­ ied by Bernhard (1 982b ) were receiving mainten­ strom (1983) who indicated that once-daily admin­ ance systemic corticosteroids, they were evenly dis­ istration was associated with no loss of efficacy, tributed between the high- and low-dose auranofin and that initial response could be maintained with treatment groups, the dosage of corticosteroid was half of the dosage given during the first 6 months kept constant for the initial 12 weeks of the study, of the study. Similarly, in the majority of the and no subsequent increase in their dosage was patients treated by Goobar and Horton (1983), the permitted. Auranofin has no direct analgesic activ­ initial improvement seen following auranofin 3mg ity, and therefore concomitant administration of twice daily for 3 to 4 ~onths was maintained with non-steroidal anti-inflammatory drugs was permit­ reduced daily doses (usually 4mg). ted in all studies. Champion et al. (1982) allowed Recent open studies have suggested that aur­ drug or dosage changes in non-steroidal anti-in­ anofin may be particularly useful for active disease flammatory regimens when side effects became of recent onset that has not progressed beyond ana­ troublesome. tomical stages I or II (Bandilla et aI., 1983b; Ciompi In the dose-establishment studies, antirheu­ et aI., 1983; Homma et aI., 1982; Schorn, 1982, matic efficacy was most often manifested by de­ 1983). creases in duration of morning stiffness and num­ Withdrawal of auranofin treatment due to inef­ ber of tender or swollen joints. Only I study ficacy or side effects has been necessary in 0 to 33% reported improvement in activity index (Schatten­ of patients in the open studies, but there is little kirchner and Delattre, 1983), and only 2 studies evidence of any clear association between the in­ (Bernhard, 1982b; Schattenkirchner and Delattre, cidence or severity of side effects (section 4) and 1983) demonstrated improvement in articular in­ serum or blood gold concentrations (Hafstrom, dex. Decreases in 19A and IgM occurred at 3 and 1983; Weisman and Hannifin, 1979). 6 months in patients receiving auranofin 6mg daily, The progression of erosive disease during aur­ but only after 6 months in patients treated with anofin therapy was also studied in the open trials 2mg daily. Similarly, IgG decreased after 6 months of Bandilla et al. (1982) and Homma et al. (1982). in patients receiving 6mg daily, but not at all in The results are discussed in section 3.1.6. the group treated with 2mg daily (Bernhard, 1982b). Only Finklestein et al. (1980) reported significant 3.1.2 Dose Establishment Studies decreases in rheumatoid factor titre. Several open and double- or single-blind studies Generally a dosage of auranofin 6mg daily was have been conducted to determine the dosage of compared with 2mg or 3mg daily, and no signifi­ auranofin which provides optimum therapeutic cant differences between the therapeutic efficacy of benefit with minimum toxicity (table VI). the dosage regimens were found (Baldassare et aI., Table VI. Summary of studies comparing different dosage regimens of auranofin (A F) in the treatment of active rheumatoid arthritis >- ..,~ Ol ::l Reference Number of Study design Antirheumatic efficacyd 0 patientsb Dose and dosage ~ duration time to grip no. of articular rheuma- index of ESR relative clinical ? [study schedule of morning onset of strength tender/ index toid function' efficacy of regimens >- duration, auranofin '"tl stiffness fatigue swollen factor studied .., months] 2 joints titre 3' :;. Baldassarre et al. 24 [3-12] dbC Ol ,:;:l (1980)a Group I: 3mg bid + + No conclusions ~ Group II: 1mg bid stated '"<: ". Bernhard (1982b) 230 [6] dbC ~ [also see Group I: 2mg qd ++ ++ ++ ++/++ ++ + + 2mg qd "" 6mg qd Weiss, 1983] Group II: 6mg qd ++ ++ ++ ++/++ ++ + +

Calin et al. (1982) 106 [6] dbC [also see Group I: 1mg qd 0 0 9mg qd > lmg qdO Weiss, 1983] Group II: 9mg qd

Champion et al. 12 [6] sb, r (1982) All pts 6mg qd x 1 month, then Group I: 2mg qd ++ 0 ++/++ 0 ++ ++ 2mg qd "" 3mg qd Group II: 3mg qd ++ ++ ++/++ 0 ++ 0

Champion et al. 31 [6] db (1983) All pts lmg qd x 1 month, then Group I: 4mg qd ++ ++ ++/++ ++ ++ 4mg qd = 6mg qd Group II: 6mg qd ++ ++ ++/++ ++ ++ = 8mg qd Group III: 8mg qd ++ ++ ++/++ ++ ++

Finklestein et al. 28 [3] op (1980) Group I: 2mg qd + +/+ ++ + 3mg bid or tid > Group II: 4mg qd 2mg qd or 4mg qd Group III: 3mg bid Group IV: 3mg tid

Gottlieb et al. 18 [6] db (1980a,b)a Group I: 3mg bid x 8 ++ ++/++ + 0 lmg qd "" 3mg qd wks, then 3mg qd x 18 wks .... 0 N Auranofin: A Preliminary Review 403

"E "0 II)Q) 1980; Bernhard, 1982b;I 982b; Champion et aI., 1982, :c:0 E Ol II)Q) 1983; Gottlieb et aI., 1980a). This could be attrib­ E >o C') C. utable in part to the small numbers of patients '"II 5 "0 studied by Baldassare et al. (1980) and Gottlieb et c-0" II Ol + al. (1980a,b), but 230 patients were evaluated by E u:;-~ <0co o ...ic Bernhard (1982b). Alternatively, the 6- to 12-month ci6 Q)II) E v Q)II) treatment periods may have been too brief to fully a.0. 1;~ assess the relative efficacy and toxicity of the dif­ + Ol C. o + E 5 ferent treatment regimens. Champion et al. (1983) 1\ o oi cc: analysed 6-month data by use of multivariate pro­ Vlm Ol c:C o E o cedures incorporating trend analysis and found no 0.a. ~ Vlm II:c:: ~ significant relationship between the dose of aur­ ~ UlC/) 'OJ Ww "0 "E Q) anofin administered or steady-state serum gold Q) II) .!: U ~ CD 'c concentration and antirheumatic response. Failure a.0. Vl .r::. OJ - o a; ~ of the technique to discriminate between the 3 dos­ :J U "0 ~ ~;:=::t= ages was attributed the narrow dosage range (4 to i:i Q)"'" >. 8mg) being investigatedinvestigated. . + ..5 .2: 0') ~ + t:c <0:"0 Diarrhoea was the most common side effect re­ 8.8. ~m~ Diarrhoea was the most common side effect re­ ~~ -g~~ ported and appeared to be dose related (Bernhard, + ~:6 !.~II. 1982b; Calin et aI., 1982), while dermatological re­ :t:t. ..,c: -00-0- o OJ~ ~-;:c~ actions (usually rash) were most likely to result in 'T.J Q) 0 C .- 0 .Q"O v'>~v CD c :.= n::I withdrawal of auranofin treatment (Bernhard, o.~ s~"Oo. 1982b; Calin et aI., 1982; Champion et aI., 1982). 80 #~IIB :;0 ~_"8-ti In the comparison by Bernhard (l982b), the with­ ~"O .-o~C::-~ drawal rate due to side effects was similar in ~~~C".~~:; Q)e~CJ'S;O­ >-'EeE+=OII­ patients treated with either 2mg or 6mg daily, but ~ocno>u ~ adverse gastrointestinal reactions occurred more .g~ci~g-E - Q) Q) r--.. - .- Q) often with the higher dosage. ~ .r::. E '" ";: 1il 1; often with the higher dosage. o~a;-o"O.~o. Withdrawals due to drug inefficacy have ranged + + cC~C"~EE + + ~2~0).~.g:; from 25 to 57% (Calin et ai.,aI., 1982; Champion et ~~o~g~~ -5ro.c-..~~.g ai.,aI., 1982) with an apparent lack of efficacy asso­ X "0 .'~.8~t1l ~ 0" ciated with low dosages of auranofin (I(1 to 3mg :g OJ -0:'2-0:2 5Q)rn£coo~~+ et aI., IJ980a,b). 980a,b). However, other investigators (e.g. ~£~ ..:..:::: ~ - Jg .~ '" ~ e ~ c. e e 5=~~~~1I&. similar proportion of the 230 patients treated with

initial dosage for subjective and objective clinical 26.4% of auranofin and placebo-treated patients improvement. experiencing side effects, respectively. As with most other antirheumatic agents, in­ dividual dosage adjustments may be necessary with 3.1.4 Comparisons with Sodium auranofin (Weiss, 1983). However, auranofin 6mg Aurothiomalate daily may be an appropriate initial dose in most A number of open, placebo-controlled, and patients with rheumatoid arthritis. blinded comparisons of auranofin and sodium aurothiomalate (gold sodium thiomalate) have been 3.1.3 Auranofin Compared with Placebo reported (table VII). Unfortunately, most of these In placebo-controlled studies the clinical effi­ comparative studies have been published in ab­ cacy of auranofin has generally been shown to be stract form only, or as preliminary findings from superior to that of placebo. In two 6-month double­ a trial still in progress. Therefore, little definitive blind parallel studies of 152 and 18 patients [Wen­ data regarding efficacy and tolerability associated ger et aI., 1983a (see also Katz et aI., 1982) and with these 2 agents are available. Full reports of Morteo et aI., 1983, respectively] and a 3-month these trials and other well-designed comparisons single-blind crossover study of 8 patients (Finkel­ between auranofin and sodium aurothiomalate will stein et aI., 1976), auranofin 3mg 2 or 3 times daily be necessary before the relative role of these 2 drugs significantly decreased the number of tender and in the treatment of rheumatoid arthritis is known. swollen joints and the duration of morning stiff­ The comparative studies of auranofin and sod­ ness, and increased grip strength compared with ium aurothiomalate have been conducted with placebo. Auranofin 3mg twice daily also produced patient populations averaging 70 patients each a significant decrease in IgA, IgG, IgM and eryth­ (range 24 to 208). Generally, auranofin 6mg in rocyte sedimentation rate 3 and 6 months after single or divided daily doses has been compared commencement oftherapy (Finkelstein et aI., 1976; with sodium aurothiomalate 50mg weekly, and Wenger et aI., 1983a). Another 6-month, random­ these medications have been added to pre-existing ised double-blind parallel comparison of auranofin regimens of non-steroidal anti-inflammatory drugs. and placebo has been reported (Palmer et aI., 1983). Most of the studies have been designed to be 1 to In this study, the high dropout rate (50%) in both 2 years in duration, but results reported to date patient groups (each consisting of 10 patients) pre­ have usually described the safety and efficacy as­ cluded any meaningful statistical analysis of effi­ sociated with each agent only during the initial 6 cacy data; however, a greater number of intra-ar­ to 12 months of therapy or in only a portion of ticular corticosteroid injections were required by the total number of patients. patients receiving placebo than those administered Generally, patients were predominantly female auranofin. Neither agent reduced patient depend­ (male to female ratio 1 : 2 to 3), 45 to 55 years of ability on non-steroidal anti-inflammatory agents. age, and had symptoms of classic or definite rheu­ In the study by Wenger et al. (1983a), side effects matoid arthritis of 5 to 6 years duration. Although developed in about 58% of patients treated with minor differences in severity of duration of disease auranofin and in approximately 27% receiving pla­ were reported between treatment groups, none was cebo, and necessitated treatment withdrawal in 5% statistically significant. Three studies (Barraclough and 3%, respectively. et aI., 1982; Schattenkirchner et aI., 1982; Ward et In a multicentre double-blind study of 244 aI., 1983a,b,c,d) allowed participation by patients patients (Abe et aI., 1984), auranofin 6mg daily for taking systemic corticosteroids (although dosages 24 weeks resulted in greater mean 'global efficacy' of these agents were limited), and another (Menard (p < 0.00 I) and 'global utility' (p < 0.05) ratings et aI., 1982) permitted restricted use of intra-arti­ than did placebo treatment. 'Global safety' ratings cularly injected corticosteroids during treatment for each treatment were similar, with 37.1% and with auranofin or sodium aurothiomalate. Menard Auranofin: A Preliminary Review 405

et al. (1982) and Smith et al. (1983) specifically ex­ Lee (1981) reported an approximate 25% remission cluded patients who had received rheumatoid­ rate in both auranofin and sodium aurothiomalate remitting agents within the previous 6 months, treatment groups. These data may not be truly rep­ whereas Ward et al. (I 983a,b,c,d) excluded patients resentative, however, since the number of patients who had previously received gold compounds or in each treatment group was small (8) and the cytotoxic agents, and Davies et al. (1983) excluded treatment time was relatively brief (26 weeks). those treated with disease-modifying agents or Smith et al. (1982, 1983) determined the severity steroids. of disease at 6-monthly intervals in patients treated In the studies where statistical analysis of patient with auranofin or sodium aurothiomalate for 18 response was presented, sodium aurothiomalate was months. At 6 and 12 months, when the treatment at least as effective as auranofin as evidenced by groups were largest and most representative, the the level of significance of the changes in the as­ remission rate in the sodium aurothiomalate-treated sessment criteria (Komatsubara et aI., 1984; Lee, patients was 2 and 1.7 times, respectively, that in 1981; Lewis et aI., 1982, 1983; Menard et aI., 1982; patients receiving auranofin. After 12 months of Smith et aI., 1983; Ward et aI., 1983b,c,d). Lee treatment, there were no longer any patients with (1981) reported that response to auranofin was severe disease in either group. more rapid than to sodium aurothiomalate [7.7 or Withdrawals because of inefficacy have gener­ 6.0 weeks (depending on dose of auranofin) versus ally been equal in the two treatment groups, al­ 9.4 weeks], although Lewis et a1. (1982, 1983) noted though Menard et a1. (1982) reported that with­ an earlier response in the patients treated with sod­ drawals were twice as frequent with auranofin as ium aurothiomalate. The conflicting nature ofthese with sodium aurothiomalate, and Ward et ai. data was probably due to differing criteria used to (1983a,b,c,d) noted 5 withdrawals due to inefficacy gauge response: Lee defined response time as the in the auranofin group and none in the patients occurrence of 'clinical symptomatic improvement' treated with sodium aurothiomalate. whereas Lewis and co-workers used more objective In the dosages administered in the comparative parameters (decreases in erythrocyte sedimenta­ studies, auranofin and sodium aurothiomalate were tion rate, C-reactive protein, and pain scores) to generally associated with the same overall inci­ assess duration of response. Although many para­ dence of side effects (Davies et aI., 1983; Lee, 1981; meters of disease activity were usually measured, Kaik et aI., 1983; Menard et aI., 1982). However, the efficacy of either gold compound was most often side effects necessitating withdrawal of treatment manifested by decreases in duration of morning were generally more frequent with sodium auro­ stiffness, pain scores, number of tender joints, joint thiomalate than with auranofin (table VII; section tenderness score, activity and articular indices, and 4). Mucocutaneous side effects were more frequent improvements in physician's global assessment and and/or severe within the patient groups treated with feeling of wellbeing (Lewis et aI., 1983; Menard et sodium aurothiomalate (Jamer et aI., 1983; Kaik aI., 1982; Smith et al., 1983; Ward et aI., 1983b,c,d). et aI., 1983; Menard et aI., 1982; Smith et aI., 1982; Both auranofin and sodium aurothiomalate de­ Ward et aI., 1983a,b,c,d), whilst gastrointestinal side creased erythrocyte sedimentation rate, rheuma­ effects were more frequent during auranofin therapy toid factor titre and C-reactive protein in several (Jamer et aI., 1983; Menard et aI., 1982; Schatten­ studies; however, the decreases occasionally reached kirchner et aI., 1982; Smith et aI., 1983). a higher level of statistical significance following Patients with rheumatoid arthritis previously sodium aurothiomalate therapy (Keegan et aI., controlled by sodium aurothiomalate have been 1983; Lewis et aI., 1982; 1983; Smith et aI., 1983). 'crossed over' to treatment with auranofin with Unfortunately, few comparative trials have re­ varying results. The transfer (usually from sodium ported the rates of remission associated with the aurothiomalate 50mg every 2 to 4 weeks to aur­ parallel administration of these gold compounds. anofin 3mg twice daily) was not associated with Table VII. Summary of non-blinded, placebo-controlled, and blinded comparative studies of auranofin (AF) and sodium aurothiomalate (ATM) in the treatment of active ;I> rheumatoid arthritis '"~ :3 0 ::tl Reference No. of patients Study Dose and dosage No. of patients and F.lelative Relative number No. of ? (planned study designC schedule duration at time of antirheumatic and/or severity of withdrawals ;I> duration) efficacy evaluation efficacy side effects due to side 'tl effects a 3' S' Non-blinded comparisons I» ... Keegan et al. (1983) 37 pts AF 3mg bid 25 pts at 6 months AF < ATM .,' e AF 1 '< :;tl (1 year) ATM 50mg q wk ATM 3 ... < x 20 wks, then iii' 50mg q month ~

Komatsubara et al. 83 pts AF 6mg qd 83 pts at 24 weeks AF", ATM AF < ATM AF 2 (1984)8 (Not specified) ATM 10-50mg ATM 8 q 1-2 wks

Lee (1981) 24 pts GRP I: AF 3mg bid 24 pts at 26 wks AFt '" ATM AFt", ATM AF 0 [also Moon et aI., 1981]8 (26 weeks) x 4 wks, then 2mg ATM 1 bid x 22 wks GRP II: AF 3mg bid x 26 wks

GRP 111:ATM 10mg q wk x 2 wks, 25mg 3rd wk, then 50mg weekly thereafter

Menard et al. (1982)b 120 pts AF 3mg bid Study completed AF < ATM AF < ATM AF 7 [also Thompson et aI., (2 years) ATM 50mg q wk ATM17 1981,1983]0 x 20 wks, then 50mg q month to 52 weeks

Smith et al. (1983) 60 pts AF 3mg bid 29 pts at 96 wks AF';; ATM AF < ATM AF 0 [also Smith et aI., 1982]b (up to 96 weeks) ATM 50mg q wk ATM 6 3rd-24th wk, then monthlyd

Tvede and Strandberg 30 pts AF 3mg bid 16 pts at 48 wks AF", ATM AF'" ATM AF = ATM (1983)b (48 weeks) ATM 50mg q wk

~ a- ~ Placebo-control/ed comparisons :::., Davies et al. (1983)b 30 pts AF 3mg bid 26 pts at 9 months AF;;' PL AF'" ATM PL 0 ::I'" 0 (1 year) ATM 50mg q wk x ATM;;' PL AF 0 ~ ? 6 mos, then 20-50 AF '" ATM ATM 1 mg q month ~ .,." Lewis et aI., (1982)a 90 pts AF 3mg bid 66 pts at 24 weeks AF;;' PL AF '" ATM PL 0 2 [also Lewis and Capell, 3' (Not specified) ATM 50mg q wk ATM> PL AF 4 5' 1983) AF < ATM ATM 7 ~'" Prouse and Gumpel 30 pts r, db (PL AF 3mg bid 22 pts at 1 year AF> PL AF'" ATM PL 0 it! (1983)b (2 years) <: com pari- ATM 50mg q wk ATM> PL AF 3 '";:;).

[also Prouse et aI., son only) AF < ATM ATM 4 ~ 1981)b

Ward et al. (1983b) 208 pts r, db AF 3mg bid 161 pts at 20 weeks AF> PL AF < ATM PL 1 [also Ward et aI., (21 weeks) ATM 50mg q wk ATM> PL AF 5 1983c,d; Williams, 3rd-2Oth wkd AF '" ATM ATM 22 1982)a.b

Blinded comparisons Barraclough et al. (1982)b 42 pts r, sb AF 3mg bid 14 pts at 1 year .. .. AF < ATM AF 1 [also Barraclough et al. (1 year) ATM 50mg q wk ATM 6 1983)b x 20 wks, then 50mg q 3 wks

Jarner et al. (1983)b 45 pts r, db AF 3mg bid 14 pts at 1 year AF", ATM AF '" ATM AF 6 (1 year) ATM 50mg q wk ATM 9 3rd-24th wk, then q 2-4 wksd

Schattenkirchner et al. 121 pts r, db AF 6mg qd 68 pts at 48 AF '" ATM AF 17 (1982)b (1 year) ATM 50mg q wk weeks ATM 28 [also Kaik et aI., 1983; 3rd-24th wk, Muller-Fassbender et al. then monthlyd 1983; Rau et aI., 1983)b

a Study reported in abstract form only. b Preliminary report of study still in progress. c r = randomised; db = double-blind; sb = single-blind; PL = placebo. d ATM 10 or 20mg 1st week, 20mg 2nd week. e An ellipse indicates insufficient data exists for efficacy or side effect evaluations. Efficacy and tolerability rating combining both auranofin groups. +> 0 ---l Auranofin: A Preliminary Review 408

worsening of disease activity in one study (Wenger Auranofin 6mg daily has been compared with et aI., 1983b), whereas a subgroup of the patients D-penicillamine 150 to 750mg daily (Astaldi et aI., of Berry et al. (1983) [usually those with more ac­ 1983; Barraclough et aI., 1983; Felix-Davies et aI., tive disease at the commencement of treatment] 1982, 1983; Franchimont et aI., 1983; Scott and withdrew from auranofin therapy due to worsening Huskisson, 1981), aurothioglucose (Van Riel et aI., of their rheumatoid symptoms. Of the II patients 1983b,c), and levamisole 150mg weekly (Scott and of Parke et al. (1983) who were stabilised on sod­ Huskisson, 1981) in open and single-blind trials in­ ium aurothiomalate and later switched to auran­ volving relatively small numbers of patients. No ofin, only 4 completed 1 year of treatment. Most consistently significant differences in efficacy have patients withdrew due to inefficacy or toxicity, as been detected, with all drugs producing improve­ did the remaining patients in their second year of ment in articular index, morning stiffness, joint treatment. The side effect incidence (except aur­ swelling, and pain in some patients. Side effects anofin-induced diarrhoea) in patients who toler­ tended to be more troublesome with D-penicillam­ ated sodium aurothiomalate and continued to re­ ine and aurothioglucose than with auranofin, and ceive the drug, generally did not differ from that drug withdrawals due to inefficacy have occurred in patients who had been transferred to auranofin. more commonly with auranofin. Wessel and Davis (1983) administered a cu­ In a randomised, single-blind study (Dequeker mulative dose of at least Ig sodium aurothiomalate et aI., 1983a,b) and a double-blind multicentre trial (mean duration of treatment not specified) to 6 [Khan et aI., 1983 (see also Sany et aI., 1981 )], aur­ patients who had failed to respond to auranofin anofin 3mg twice daily was shown to have less 3mg twice daily for 20 weeks or more. Only I antirheumatic activity than sodium aurothiolpro­ patient manifested modest improvement when panolsulphonate 100mg weekly. In the 40 patients switched to the parenteral gold compound. Al­ of Dequeker et al. (1983a,b), auranofin caused sig­ though further studies are required, the results in nificant improvement in duration of morning stiff­ this small group of patients suggest that changing ness, number of tender and/or swollen joints, im­ from oral to parenteral gold treatment (when the munoglobulin concentrations, and articular and former is ineffective) may not offer patients sig­ activity indices. In addition to these parameters, nificant additional therapeutic benefit. sodium aurothiolpropanolsulphonate also im­ proved mean pain scores and erythrocyte sedi­ 3.1.5 Comparisons with Other Agents mentation rate. Of the 60 patients of Khan et al. Limited data are available from an interim re­ (1983) treated with auranofin, only the articular in­ port of a 48-week, randomised, single-blind com­ dices and the number of swollen joints were im­ parison of auranofin 3mg twice daily and hydroxy­ proved at 12 months, while these measurements chloroquine 200mg twice daily (Bird et aI., 1983). plus activity index, number of tender joints, grip Only a few of the 40 patients have completed the strength, walk time, pain score, duration of morn­ trial; however, auranofin decreased concentrations ing stiffness, time to onset of fatigue, general of IgM, IgG, and IgA, and both agents increased wellbeing, and erythrocyte sedimentation rate were grip strength. Hydroxychloroquine also increased improved by sodium aurothiolpropanolsulphonate. haemoglobin concentrations (which remained de­ Withdrawals due to sodium aurothiolpropanolsul­ creased in auranofin patients) and decreased C-re­ phonate side effects greatly exceeded those due to active protein, erythrocyte sedimentation rate, auranofin in one study (11 and 1, respectively) plasma viscosity, and platelet concentrations in a [Dequeker et aI., 1983a,b], whereas auranofin limited number of patients. Side effects have been caused more withdrawals due to side effects in the more frequent in the auranofin group, as have been study of Khan et al. (1983) [11 vs 7 patients]. With­ the withdrawals due to side effects or inefficacy (7 drawal rates due to inefficacy were approximately I'crsus I patient). equal for both agents in either study. Auranofin: A Preliminary Review 409

Further well-designed studies in adequate num­ (1977), a system which involves the scoring of in­ bers of patients are needed to determine the rela­ creases in bone erosion and joint space narrowing tive efficacy and tolerability of these potentially from hand and foot radiographs. To assess the pro­ disease-modifying drugs. gression of osteoporosis in patients with rheuma­ toid arthritis, Schorn (1983) determined the area 3.1.6 Effects of Auranofin on Radiographically index [(outside diameter of the second metacarpel Detected Progression of Rheumatoid Disease bone of the right hand)2 - (the inside diameter)2 In rheumatoid arthritis, the radiographic find­ ... both measured at the bone midpoint] from hand ings of erosion, cartilage loss, and joint destruction radiographs which allowed assessment of the cor­ appear to correlate well with the clinical evaluation tical bone diameter. This, in turn, is known to cor­ of the patient, and may have prognostic signifi­ relate well (r = 0.85) with the ash weight of bone cance regarding the course of the disease (Genant, (Exton-Smith et aI., 1969). Gofton and O'Brien 1983). Although there is some evidence in favour (1982, 1983) and O'Brien (1981) utilised a rating of a 'disease-modifying' activity for injectable gold system in which the erosion rates experienced prior compounds and cyclophosphamide, there exists no to treatment with auranofin were used to predict definitive proof that any antirheumatic agent cur­ the rate of erosion that would have occurred if rently in use is capable of preventing or retarding treatment had not been given. Although the rate joint damage in rheumatoid arthritis (Iannuzzi et of erosive change predicted by the model was sim­ aI., 1983; Larsen et aI., 1983). The radiographic ilar to that seen in placebo-treated patients in other studies performed to assess the effects of auranofin clinical trials, further testing of this model under on cartilage and/or bone loss (table VIII) have en­ placebo-controlled conditions is required to deter­ countered some of the same methodological diffi­ mine its validity. culties which arose in previous studies of other In several studies (Gofton and O'Brien, 1982, antirheumatic agents (Larsen, 1983; Muller-Fass­ 1983; Homma et aI., 1982; O'Brien, 1981) the data bender, 1983). There appears to have been little or of the effects of auranofin have been compared with no agreement nor any accepted standards among those derived from earlier trials (The Cooperating the investigators for the location, the method of Clinics Committee of the American Rheumatism scoring, or the proper statistical analysis of joint Association, 1973; Empire Rheumatism Council, space narrowing or osseous lesions. Also, most of 1960) with sodium aurothiomalate or cyclophos­ the study groups were small (15 to 37 patients) and phamide. However, the lack of information re­ were studied over relatively brief time spans (12 to garding the homogeneity of the treatment groups 18 months). Finally, non-steroidal anti-inflamma­ casts doubt on the validity of such comparisons. tory agents and/or steroids [which also have as yet In a I-year parallel study in 59 patients (Schorn, undefined effects on radiological deterioration 1983) and a 3-year parallel study in up to 36 (Iannuzzi et aI., 1983)] were administered to most patients (Smith et aI., 1983), auranofin 6mg daily patients. Therefore, the data resulting from studies in single or divided doses was compared with D­ to determine the radiological progression of rheu­ penicillamine 750mg daily and sodium aurothio­ matoid arthritis following treatment with aurano­ malate 50mg weekly, respectively. Although both fin must be interpreted with considerable caution. drugs produced similar improvement in hand Radiographic studies have mostly involved function, auranofin therapy, unlike that of small to moderate numbers of patients (15 to 83), D-penicillamine, did not result in the reversal of most of whom received auranofin 6mg daily in the rheumatoid-associated osteoporotic process single or divided daily doses over a period of 12 (Schorn, 1983). Smith et ai. (1983) noted that the to 18 months. rate of erosion was decreased by auranofin or sod­ The most common assessment method used in ium aurothiomalate only following 1 year of treat­ the radiographic studies was that of Larsen et ai. ment with either agent, and that this effect was not Table VIII, Summary of radiographic studies conducted to determine the effects of auranofin (A F) and other disease modifying agents (PL = placebo; DPN = D-peni­ ;I> cillamine; ATM = sodium aurothiomalate) on the progression of rheumatoid-induced osteoporosis, joint narrowing, and erosive disease '"OJ :: o Reference No. of patients Dose of Study Assessment criteria Significant findings/conclusions ~ ? (duration of auranofina designb ;I> study) "0 :l Bandilla et aL (1982) 15 pts (12 6 mg/day qd Not x-rays assessed by method of Larsenc Majority of films unchanged from 3' months) specified pre-treatment. Progression of :;. ~ erosion occurred in some cases, .:! and correlated well with clinical ;Al r> status of patient <: (ii' :!; Gotton and 0' Brien 143 pts Dose not 1,2,4 Rate of progression of erosive disease Both readers found rate of (1983) (12 and 24 specified predicted by assessment of erosion prior to progression of erosive disease to [see also Gofton and months) therapy (,placebo model'). Severity of be less (p < 0.01) during AF therapy O'Brien, 1982; Gofton erosive disease scored for each finger joint, than that predicted by the 'placebo et aI., 1983) individual carpel bone, radius, and ulna model'

Homma et aL (1982) 37 pts 3mg bid Number of new erosions/patient/month Two readers determined an average

(~12 weeks) determined from assessment of joints on 0.11 and 0.14 new erosions/patient/ paired hand films month following an average 7.5- month treatment period

O'Brien (1981) 68 pts 6 mg/day (or less) 1, 2 'Placebo model' predicted as above (Gotton 4,91 mean erosions/year predicted (18 months) and O'Brien, 1983). by 'placebo model' Number and severity of erosions scored in 0.66 mean erosions/year (p = 0.02) every joint of hand and wrist following 1 year AF therapy, and 0.5 mean erosions/year after 18 months

Weisman et aL (1982) 15 pts 3-9 mg/day 1,3 Clinical response graded as: Three patients showed sustained (4 years) (most patients on - sustained improvement improvement, 7 unsustained 4mg) - initial, but unsustained improvement improvement, and 5 no - no improvement. improvement. No joint space x-rays assessed by method of Larsenc narrowing occurred in any response group. Only 1 of 2 readers found a significant correlation between clinical response and change in erosive score

+> o Comparative studies c» "1 Larsen et al. (1983) 83 pts AF Doses not 3, 4 Modified method of Larsend Of pts treated with AF, 1M gold, or ::s'" 0 73 pts '1M' gold specified PL, 57.8, 71.6 and 36.3% had no ;::!l ..::s 11 pts PL progression in joint erosion, » (1 year) respectively. Only 1M gold> PL (p '"0 "1 < 0.05). 48.2, 67.6, and 27.2% 2 showed no worsening of mean joint :;.3 grade, respectively. AF < 1M gold> PL (p < 0.025). ,:;I'" ;.::I

Schorn (1983) 17 pts AF AF 6 mg/day Ash weight of bone estimated by Metacarpal index increased (p < ;;;.'"-<

42 pts DPN DPN 750 mg/day metacarpal index measurement from hand 0.0005) by DPN and decreased (p < ~ (1 year) films. Hand function determined by ability to 0.025) by AF, indicating reversal of perform daily activities demineralisation by DPN. Functional improvement DPN ;. AF

Smith et al. (1983) 16 pts AF AF 3mg bid 3 methods of scoring: AF (p < 0.01) and ATM (p < 0.004) [see also Smith et al. 20 pts ATM ATM 50mg - No. of bone defects/erosions and joint decreased rate of erosion 1982] (up to 72 weeks) weekly space narrowing (hand films only) development at 1 year only. No - Right hand carpometacarpal ratio changes at 6, 18, or 27 months. measured (not all patients)" Joint space narrowing and - Method of Larsenc osteoporosis measurements were unchanged by both drugs

a Or dose of agent compared to auranofin, where applicable. b 1 = x-ray films interpreted by 'blind' radiologist and read randomly as regards to sequence (pre- or post-treatment); 2 = reader blinded as to right or left hand nature of film; 3 = retrospective; 4 = multicentre. c Method of Larsen = scoring system based on increasing erosion and joint space narrowing on hand and foot films. d Modification included removal of joint-space narrowing assessment and reduction of the number of total joints assessed. e The carpometacarpal ratio is calculated by dividing the lengths of the carpus by the third metacarpal and correlates highly with recognised radiographic stages of rheumatoid arthritis (Trentham and Masi, 1976). +> Auranofin: A Preliminary Review 412

persistent. Finally, in a placebo-controlled com­ clarify its potential role in the treatment of this dis­ parison of auranofin and sodium aurothiomalate ease. (Larsen et aI., 1983), only sodium aurothiomalate was found to significantly decrease the progression 3.3 Other Areas of Use of joint erosion. Recent studies have shown a lack of radiologi­ In a 2-year pilot study of 13 patients with sys­ cal progression of disease following I year's treat­ temic lupus erythematosis (but without renal dis­ ment with auranofin (Ciompi et aI., 1983; Tvede ease) [Weisman et aI., 1983], auranofin 6mg daily and Strandberg, 1983); however, these studies were induced significant improvement in physician's uncontrolled and assessment criteria were not re­ global assessment of disease severity (percent ana­ ported. logue scale, 0.37 to 0.26; p < 0.013), daily pred­ In view of the sometimes questionable assess­ nisone dose (8.38 to 5.7mg daily; p < 0.027), and ment and comparative criteria, the large number serum haemolytic complement titration (64 to 80 of negative findings, and the sporadic nature of the units/ml; p < 0.001). However, other laboratory positive findings, there appears to be insufficient assessments and more objective clinical measure­ evidence to conclude that auranofin has any effect ments of disease activity were not improved com­ on the occurrence or progression of osteoporosis, pared with baseline values. joint narrowing, or erosive processes associated with Auranofin 6mg daily for i to 6 months was re­ rheumatoid arthritis. Further well-designed trials ported to have reversed the leucopenia and sple­ are required to determine more clearly whether nomegaly of 2 patients with Felty's syndrome auranofin can decrease the severity or rate of pro­ (Tumiati et aI., 1983). gression of the arthritic process. 4. Side Effects 3.2 Juvenile Rheumatoid Arthritis Auranofin has been well tolerated by most The safety and preliminary efficacy of auranofin patients, but a number of troublesome and some­ in the treatment of juvenile rheumatoid arthritis times serious side effects have been reported. In was evaluated in 21 patients (age 1.5 to 17 years) several instances, auranofin was implicated, but an in an open-ended uncontrolled trial (Brewer et al., absolute cause-effect relationship was not estab­ 1983; Giannini et aI., 1983a). Auranofin 0.1 to 0.2 lished. The nature of adverse effects with auranofin mg/kg/day over an average treatment period of 12.1 appears to be similar to that with parenteral gold months resulted in clinically significant improve­ compounds, but generally they are less severe with ment (> 25%) in half of the patients tested as meas­ auranofin (section 3.1.4). Side effects influencing ured by decreases in number and severity of swol­ the lower gastrointestinal tract are the most com­ len joints, pain on motion, and joint tenderness. mon problem with auranofin, whereas mucocutan­ Functional class was improved in 4 of the children, eous side effects have usually been most frequent and II of 16 showed greater than 25% decreases with injectable gold compounds. To date, the with­ in erythrocyte sedimentation rate. Therapy with drawal rate for adverse reactions has approximated auranofin was discontinued in I child due to inef­ 10% (Blodgett, 1983a,b). Wider clinical experience ficacy, and in 2 children because of side effects. and monitoring of side effects are needed to estab­ Although efficacy data in uncontrolled trials must lish more clearly the long term effects of auranofin. be cautiously interpreted, the response to aurano­ fin demonstrated by these patients is promising. 4.1 Gastrointestinal Effects Double-blind controlled studies of auranofin in ad­ equate numbers of patients with juvenile rheu­ Gastrointestinal side effects occur frequently matoid arthritis are needed in order to further with auranofin, 42 to 58% of patients having ex- Auranofin: A Preliminary Review 413

perienced some type of upper or lower gastroin­ Auranofin-induced diarrhoea may be controlled testinal disturbance (Ghozlan et aI., 1983; Heuer by a reduction in dose (Bandilla et aI., 1982), use and Morris, 1983; Homma et aI., 1982; Katz et aI., of variable dosage regimen (Smith et aI., 1982), ap­ 1982; Schattenkirchner et aI., 1982; Van Riel et aI., propriate symptomatic treatment (Bandilla et aI., 1983a). 1982; Hafstrom 1983), increase in dietary fibre 29 to 44% of patients on auranofin therapy have (Heuer and Morris, 1983), oral iron administration experienced loose stools or diarrhoea (Bandilla et (Van Riel et aI., 1983a) or, if all else fails, drug aI., 1982; Heuer and Morris, 1983; Heuer et aI., withdrawal (Bandilla et aI., 1982). Diarrhoea may 1983; Katz et aI., 1982; Schattenkirchner et aI., or may not recur when therapy is reinstituted after 1982; Van Riel et aI., 1983a), often accompanied temporary withdrawal (BerglOf et aI., 1978). by abdominal cramping (Baldassare et aI., 1980; Jarner and Nielsen (1983) reported 1 case of en­ Gottlieb et aI., 1980a; Van Riel et aI., 1983a). Diar­ terocolitis which had occurred secondary to aur­ rhoea secondary to auranofin may occur at any time anofin treatment (3mg twice daily; total dose in the course of treatment, but most often occurs I 68mg), characterised by abdominal pain, diar­ within the initial 2 to 3 months of administration rhoea (bloodless), high fever and dehydration. Rec­ (Heuer and Morris, 1983; Homma et aI., 1982; to scopic examination of the patient revealed an Schorn, 1982; Tvede and Strandberg, 1983; Van oedematous mucosa without ulceration, while ab­ Riel et aI., 1983a). Patients prone to diarrhoea and dominal radiographs showed an increasing dila­ cramping with auranofin usually experience these tation of the large bowel compatible with toxic effects within the initial few hours after taking the megacolon. Recovery was complete following drug, leaving the patient symptom-free for the re­ discontinuation of auranofin and treatment with mainder of the day (Van Riel et aI., 1983a). The total parenteral nutrition, corticosteroids, and anti­ incidence of diarrhoea appears to be related to the biotics. Gold-induced enterocolitis has also been size of the dose, but not frequency of administra­ reported with parenteral gold compounds (Fam et tion (Bandilla et aI., 1982, 1983b; Hafstrom, 1983), aI., 1980; Stein and Urowitz, 1976). and is apparently increased in patients of low Although most side effects occur in the lower bodyweight (Homma et al., 1982). gastrointestinal tract, epigastric pain (Bandilla et Diarrhoea secondary to auranofin has not been aI., 1982; Calin et aI., 1982), erosive gastritis (Felix­ associated with weight loss (Hafstr6m, 1983), gas­ Davies et aI., 1982, 1983) and nausea (Schorn, 1982) trointestinal bleeding (Hafstrom, 1983; Van Riel et have occurred in association with auranofin treat­ aI., I 983a), or malabsorption as determined by lac­ ment. Concomitantly administered non-steroidal tose tolerance, Schilling's test, or D-xylose testing anti-inflammatory drugs may have played an ac­ (Bandilla et aI., 1982; Van Riel et aI., 1983a). Small tive role in some of these reactions (Heuer and bowel biopsy and proctoscopy in these patients Morris, 1983). Abnormalities in taste sensation have revealed no abnormalities (Bandilla et aI., have also been reported (Bandilla et aI., 1982; 1982). The diarrhoeal stool is characterised by nor­ Homma et aI., 1982; Katz et aI., 1982). mal osmolarity, and high sodium and low potas­ sium content (Van Riel et aI., 1983a). Mild stea­ 4.2 Haematological Effects torrhoea was present in 2 patients studied by Bandilla et ai. (1982), but Van Riel et ai. (1983a) Anaemia has been reported to occur occasion­ reported normal faecal fat content in patients with ally either as a direct effect or secondary to aur­ auranofin-induced diarrhoea. The mean serum gold anofin-associated haematuria (Bernhard, 1982b; concentration in these patients was no different to Giannini et aI., 1983a). that in patients with normal stools on the same Auranofin has also been associated with a gen­ dosage, suggesting that gold absorption is not af­ eral leucopenia (Lewis et aI., 1982; Schorn, 1982; fected by diarrhoea (Van Riel et aI., 1983a). Williams, 1982), lymphopenia (Hunt and Holt, Auranofin: A Preliminary Review 414

1981), neutropenia (Calin et aI., 1982; Hunt and Berglof et a!., 1978; Giannini et aI., 1983a; Schorn, Holt, 1981) and eosinophilia (Edelman et aI., 1983; 1982), generally following at least 2 to 3 months of Williams, 1982), which in I study (Edelman et aI., therapy (Berglof et aI., 1978). Renal biopsy in I 1983) occurred in 13% of patients. Pre-existing eo­ patient who developed 4 months of haematuria sinophilia is not a reliable indicator of potential after 21 months of auranofin revealed modest focal auranofin gold toxicity (Edelman et aI., 1983). and segmental mesangial hypercellularity (Schorn, Thrombocytopenia has been reported following 1982). However, it was unclear whether these auranofin administration (Bernhard, 1982b; Katz changes were caused by auranofin or were due to et aI., 1982; Schorn, 1982; Smith et aI., 1982), al­ the underlying rheumatic disease. though it is uncommon « 0.5% of patients) [Heuer and Morris, 1983]. Once auranofin is withdrawn, 4.4 Mucocutaneous Effects platelet counts have returned to the normal range within I to 2 weeks (Bernhard, 1982b). In 3 studies (Bandilla et aI., 1982; Ghozlan et aI., 1983; Homma et aI., 1982), mucocutaneous side 4.3 Renal Effects effects occurred in 31 to 43% of patients treated with auranofin. These effects have usually been Proteinuria has occurred in many clinical trials mild and have readily resolved following a reduc­ (Bandilla et aI., 1983b; Bernhard, 1982b; Ehrlich et tion in dosage or temporary withdrawal of auran­ aI., 1979; Giannini et aI., 1983a; Katz et aI., 1982; ofin (Smith et aI., 1982). Approximately 18 and 24% Menard et aI., 1982), but it has only rarely pro­ of patients treated with auranofin have developed gressed to the nephrotic syndrome (Plaza et aI., skin rash or pruritus, respectively (Heuer and Mor­ 1982; Revach et aI., 1979). A study of approxi­ ris, 1983; Heuer et aI., 1983; Schattenkirchner et mately 600 patients receiving auranofin revealed aI., 1982). Both conjunctivitis and stomatitis have the incidence of proteinuria to be no greater than been reported to occur in approximately 10% of 5% (Heuer and Morris, 1983), but the incidence patients treated with auranofin (Heuer and Morris, was 13% in one multicentre study of 449 patients 1983; Heuer et a!., 1983; Schattenkirchner et aI., treated with auranofin 6mg daily in single or di­ 1982). Although pruritus and stomatitis are more vided doses (Band ilia et aI., 1983b). In a patient likely to occur early in treatment, conjunctivitis with auranofin-induced nephrotic syndrome, per­ appears to occur at a steady rate regardless of treat­ cutaneous renal biopsy demonstrated electron-dense ment duration (Heuer and Morris, 1983). material in subepithelial areas of kidney basement In two studies, 7 to 8% of patients have devel­ membrane and IgG immunodeposits consistent oped alopecia, particularly following prolonged with antigen-antibody complexes. These would administration of auranofin (Bandilla et aI., 1982; suggest that auranofin-induced proteinuria is a Schattenkirchner et aI., 1982). However, an ana­ hypersensitivity type of reaction. Gold was not lysis of worldwide experience with auranofin in­ found in the IgG immunodeposits, and the mech­ dicated that the usual incidence of alopecia is much anism by which gold compounds initiate deposi­ lower (approximately 2%) [unpublished data on file; tion of such complexes is unknown (Plaza et aI., Smith, Kline & French]. The severity of alopecia 1982). Mild to moderate proteinuria can be de­ has been decreased by reduction of the daily dos­ creased, or stopped in some cases, by reduction of age (Bandilla et aI., 1982). auranofin dosage (Giannini et aI., 1983a), but sev­ ere proteinuria may require 4 to 6 months to com­ 4.5 Other Reactions pletely dissipate following auranofin withdrawal (Plaza et aI., 1982; Revach et a!., 1979). Corneal and lens chrysiasis (which commonly Haematuria associated with auranofin has been occur during long term parenteral gold therapy) and reported in a few patients (Barraclough et a!., 1982; skin chrysiasis (which occurs less frequently) have Auranofin: A Preliminary Review 415

not been reported to occur following long term Usual precautions during auranofin treatment auranofin treatment (Blodgett, 1983b; Gott­ should include frequent inquiry regarding the oc­ lieb, 1982). currence of gastrointestinal disturbance, pruritus, A few instances of severe recurrent headache dermatitis, stomatitis, or conjunctivitis. Complete (Giannini et aI., 1983a) and muscle pain (Schorn, blood counts and urinalysis should be performed 1982) have been reported during auranofin treat­ prior to therapy and at least monthly thereafter. ment, and Menard et al. (1982) reported I case of Management of gold toxicity due to auranofin possible gold pneumonitis ('gold lung') associated therapy is dependent upon the type and severity of with auranofin administration. the reaction. Reversal of most gastrointestinal and mucocutaneous side effects may be accomplished 5. Dosage and Administration by temporary drug withdrawal and/or reduction in dose, whereas renal and haematological reactions, In general, it is reasonable to consider the ini­ especially when severe, necessitate drug with­ tiation of chrysotherapy in patients with definite drawal. or classic rheumatoid arthritis which continues to be active or progressive despite adequate thera­ 6. The Place of Auranofin peutic dosages of non-steroidal anti-inflammatory in Therapy drugs, intra-articular injections of corticosteroids, rest and physiotherapy (Goldman and McDonald, Therapeutic trials indicate that auranofin is an 1983; Gottlieb, 1977; Sigler, 1983; Jessop, 1979; orally active and effective drug for the treatment Kaplan, 1983; Katz, 1982; Lipsky, 1983). of rheumatoid arthritis, although available com­ In most patients, the recommended daily dos­ parative reports suggest that auranofin may be age of auranofin is 6mg administered in single or somewhat less active than sodium aurothiomalate. divided doses and taken with meals. Although Insufficient data are available to determine clearly therapeutic response with auranofin has usually the efficacy of auranofin relative to that of auro­ been observed within 3 months, some patients may thioglucose, D-penicillamine or antimalarial agents. require as long as 12 months to manifest an op­ Compared with most of these drugs, however, aur­ timum response (Heuer and Morris, 1983). If a re­ anofin is well-tolerated, side effects being less sev­ sponse has not occurred within 4 to 6 months, an ere than with parenteral gold treatment and usually increase in dosage to 9mg daily is recommended. readily controlled by a decrease in dosage. Never­ Patients on parenteral gold treatment may be theless, as proteinuria and thrombocytopenia also transferred to oral therapy without the need for occur with auranofin, routine laboratory testing is either an 'overlap' or 'washout' period (Berry et aI., required. 1983; Davis, 1983; Parke et aI., 1983; Wenger et The effect of auranofin on the radiologically de­ aI., 1983b). tected progression of rheumatoid arthritis is un­ Auranofin is contraindicated in patients who clear, but present studies suggest that auranofin may have previously exhibited enterocolitis, pulmonary be of particular use in patients with moderately ac­ fibrosis, or exfoliative dermatitis due to injectable tive disease of recent onset which is poorly re­ gold compounds. In addition, it is advised that sponsive to non-steroidal anti-inflammatory agents auranofin not be administered to patients with and other conventional therapies, before the use of progressive renal disease or severe active hepatic more toxic agents is considered. It has not yet been disease, or to patients with a history of bone mar­ clearly established whether auranofin is safe and row toxicity. It is recommended that auranofin be effective in patients who have had adverse reac­ used with caution in patients with a history of se­ tions to parenteral gold compounds. rious toxicity to parenteral gold compounds, In­ Thus, while additional well designed long term flammatory bowel disease, or atopy. studies are needed to definitively define the place Auranofin: A Preliminary Review 416

in therapy of auranofin in active rheumatoid arth­ ritis. Comparison of 2mg and 6mg daily dose. Journal of ritis, it is clear it offers a worthwhile addition to Rheumatology 9 (Suppl. 8): 149-153 (1982b). the small number of agents with disease-modifying Berry. H.: Crisp. A.1.: Douglas. R.1.: Pitt. P.: Irani. M.: Clarke. 8.: Bloom. B.: Gibson. T.1. and Panayi. G.S.: Double-blind potential. comparison of auranofin and Myocrisin in patients previ­ ously stabilized on Myocrisin: in Capell et al. (Eds) Interna­ tional Symposium on Auranofin. pp. 211-227 (Excerpta Med­ References ica. Amsterdam 1983). Bieri. D.: Champion. G.D.: Day. R.O.: Graham. G.G. and Haski. Abc. T.: Homma. M.: Shiokawa. Y.: Shichikawa. K.: Kageyama. A.L.: Measurement of subjective parameters of rheumatoid K.: Yoshizawa. H. et al.: Results of a multicenter double-blind arthritis: Development of an index of function. Australian and study with auranofin in Japan: abstracts from the 5th SEA­ New Zealand Journal of Medicine 7: 92 (1977). PAL Congress of Rheumatology. Bangkok. Jan 26 (1984). Bird. H.A.: Le Gallez. P.: Dixon. J.S.: Sitton. N.G. and Wright. Astaldi. A.: Ambanelli. V.: Barbieri. P.: Bellelli. A.: Broggini. M.: V.: Results of a comparative study of auranofin and hydrox­ Cantoni. S. et al.: Auranofin versus D-penicillamine in rheu­ ychloroquine in Capell et al. (Eds) International Symposium matoid arthritis: A multicenter controlled trial. X European on Auranofin. pp. 249-263 (Excerpta Medica. Amsterdam. Congress of Rheumatology. p. 4 Moscow June 28 (1983). 1983). Australian National Drug Information Service: Profile on auro­ Blocka. K.: Auranofin versus injectable gold: Comparison of thioglucose. Australian Journal of Pharmacy 63: 223-227 pharmacokinetic properties. American Journal of Medicine (1982). 75 (Suppl. 6A): 114-122 (1983). Baldassare. A.: Zuckner. J.: Weiss. T.: Moore. T.: Osborn. T.: Blocka. K.: Dromgoole. S.: Furst. D. and Paulus. H.: Single dose Stern. M. and Neucks. S.: Auranofin therapy in rheumatoid pharmacokinetics of ,95 Au-auranofin using a total body ra­ arthritis. Arthritis and Rheumatism 23: 651 (1980). diation counting chamber. Arthrit. Rheum. 23: 654 (1980). Bandilla. K.: Baumgarten. F. and Missler. B.: Clinical experience Blocka. K.: Furst. D.E.: Landaw. E.; Bomberg, A.; Dromgoole. S. with long term therapy of rheumatoid arthritis with oral gold and Paulus. H.E.: Pharmacokinetics of a single dose of aur­ (Auranofin): Report of an open multicenter study. Aktuelle anofin in rheumatoid arthritis. Auranofin in Rheumatoid Rheumatologie 8 (Suppl. I): 36-39 (1983a). Arthritis - 15th International Congress of Rheumatology. Paris, Bandilla. K.: Delattre. M.: Rahn. B. and Missler. B.: Long-term p.23(1981). treatment of rheumatoid arthritis with auranofin: Clinical re­ Blocka. K.: Furst. D.E.: Landaw. E.: Dromgoole. S.; Blomberg. sults with auranofin from German and international studies A. and Paulus. H.E.: Single dose pharmacokinetics of aur­ which included a comparison of once and twice daily treat­ anofin in rheumatoid arthritis. Journal of Rheumatology 9 ment: in Capell et al. (Eds) International Symposium on Aur­ (Suppl. 8): 110-118 (1982). anofin. pp. 97-114 (Excerpta Medica. Amsterdam I 983b). Blocka. K. and Landaw. E.M.: The organic gold compounds: Bandilla. K.: Gross. D.: Gross. W.: Herrlinger. J.: Kriegel. W.: Comparative pharmacokinetics: in Capell et al. (Eds) Inter­ Muller. W.: Siegmeth. W.: Tauseh. G.: Thumb. N. and Wag­ national Symposium on Auranofin. pp. 32-44 (Excerpta Med­ enhauser. E.1.: Oral gold therapy with auranofin (SK&F 39162). ica. Amsterdam 1983). a multicenter open study in patients with rheumatoid arth­ Blodgett Jr. R.C: Auranofin: Clinical studies in the United States ritis. Journal of Rheumatology 9 (Suppl. 8): 154-159 (1982). of America: in Schattenkirchner. M. and Muller. W. (Eds) Barraclough. D.: Boyden. K.: Brooks. P.: Thomas. D.: Brook. A. Rheumatology: An Annual Review. Vol. 8. pp. 158-161. and Tymms. K.: A comparative study of auranofin. gold sod­ International Gold Workshop. Munich. Jan 14-15. 1982 (Kar­ ium thiomalate. and D-penicillamine in rheumatoid arthritis: ger. Basel 1983a). A progress report: in Capell et al. (Eds) International Sym­ Blodgett Jr. R.C: Auranofin: Experience to date. American Jour­ posium on Auranofin. pp. 240-248 (Excerpta Medica. Am­ nal of Medicine 75 (Suppt. 6A): 86-89 (l983b). sterdam 1983). Bonta. 1.L.: Parnham. M.1.: Vincent. J.E. and Bragt. P.C: Anti­ Barraclough. D.: Brook. A.: Brooks. P.: Boyden. K.: Thomas. D. rheumatic drugs: Present deadlock and new vistas: in Ellis and Tymms. K.: A comparative study of auranofin. gold sod­ and West (Eds) Progress in Medicinal Chemistry 17: 186-222 ium thiomalate. and D-penicillamine in rheumatoid arthritis: (Elsevier. 1980). A progress report. Journal of Rheumatology 9 (Suppl. 8): 197- Browne. CD.: Bieri. D.: Graham. G.G.: Haavisto. T.: Champion. 200 (1982). G.D. and Walz. D.T.: Early phase clinical trial of auranofin BcrglOf. F.: Bergl6t: K. and Walz. D.T.: Auranofin: An oral chry­ in rheumatoid arthritis. Australian and New Zealand Journal sotherapcutic agent for the treatment of rheumatoid art,ltritis. of Medicine 10: 269 (1980). Journal of Rheumatology 5: 68-74 (1978). Brewer. E.1.: Giannini. E.H. and Barkley. E.: Gold therapy in the Bernhard. G.C: Auranofin therapy in rheuma~oid arthritis. Jour­ management of juvenile rheumatoid arthritis. Arthritis and nal of Laboratory and Clinical Medicine 100: 167-177 (I 982a). Rheumatism 23: 404-411 (1980). Bernhard. G.C: Auranofin treatment for adult rheumatoid arth- Brewer Jr. E.1.: Giannini. E.H. and Person. D.A.: Early experi- Auranofin: A Preliminary Review 417

ences with auranofin in juvenile rheumatoid arthritis. Ameri­ Davis. P.: Harth. M. and Menard. H.: A comparative study of can Journal of Medicine 75 (Suppl. 6A): 152-156 (1983). myochrysine (NATM) and auranofin (Au) in the treatment Calin. A.: Saunders. D.; Bennett. R.; Jacox. R.; Kaplan. D.; O'Brien. of RA. Annals of the Rheumatic Diseases 40: 205 (1981). W.: Paulus. H.E.; Roth. S. and Weiss, T.: Auranofin: Img or Davis. P.: Johnston. C: Miller. CL. and Wong. K.: Effects of gold 9mg'? The search for the appropriate dose. Journal of Rheu­ compounds on the function of phagocytic cells. II. Inhibition matology 9 (Suppl. 8): 146-148 (1982). of superoxide radical generation by tripeptide-activated poly­ Caruso. I.: Montrone. F.: Fumgalli, M. and Greco, M.: Auranofin, morphonuclear leukocytes. Arthritis and Rheumatism 26: 82- a new orally administered gold compound, in the treatment 86 (1983). of rheumatoid arthritis: A two-year clinical and pharmaco­ Davis. P.: Johnston. C: Miller. C and Wong, K.: The effect of kinetic study: in Auranofin in Rheumatoid Arthritis, pp. 13- gold compounds on the respiratory burst of phagocytic cells. 17. 15th International Congress of Rheumatology, Paris, June Arthritis and Rheumatism 25 (Suppl. 4): SI31 (1982a). 21-27 (1981). Davis. P.: Miller. CL. and Russell. A.S.: Effects of gold com­ Caruso. I.: Montrone, F.: Fumagalli, M.: Greco, M.: Panzarasa, pounds on the function of phagocytic cells. Suppression of R. and Longatti. S.: An Italian open study on auranofin: in phagocytosis and the generation of chemiluminescence by Capell et al. (Eds) International Symposium on Auranofin. polymorphonuclear leukocytes. Journal of Rheumatology 9 pp. 346-349 (Excerpta Medica. Amsterdam 1983). (Suppl. 8): 18-24 (1982b). Champion. G.D.: Bieri. D.: Browne. CD.: Cairns. D.: Day. R.O.: Davis. T.: The use of aura nofin in the management ofthe patient Graham. G.G.: Harris. G.: Jones. H. and Sambrook. P.N.: with rheumatoid arthritis. X European Congress of Rheu­ Determination of response of individual patients with rheu­ matology. p. 8 Moscow. June 28 (1983). matoid arthritis to auranofin: in Capell et al. (Eds) Interna­ Dequeker. J.: Francx. L. and Deckers. Y.: Comparison of oral tional Symposium on Auranofin. pp. 278-291 (Excerpta Med­ gold (auranofin) and injectable 'gold (allochrysine. gold sod­ ica. Amsterdam 1983). ium thiopropanolsulphonate) treatment in patients with rheu­ Champion. G.D.: Bieri. D.: Browne. CD.: Day. R.O.: Graham. matoid arthritis: A single-blind study: in Capell et al. (Eds) G.G.: Haavisto. T.M.: Sambrook. P.N. and Vallance. J.B.: International Symposium on Auranofin. pp. 156-164 (Ex­ Auranofin in rheumatoid arthritis. Journal of Rheumatology cerpta Medica. Amsterdam 1983a). 9 (Suppl. 8): 137-145 (1982). Dequeker. J.: Francx. L. and Vanschoubroek. K.: Auranofin ver­ Champion. G.D.: Bieri. D.: Browne. CD.: Graham. G.G. and sus Allochrysine: A study of safety and efficacy of oral and Haavisto. T.M.: Auranofin dose-plasma gold concentration­ parenteral gold therapy in rheumatoid arthritis. X European response relationships in rheumatoid arthritis. Auranofin in Congress of Rheumatology. p. 3 Moscow. June 28 (1983b). Rheumatoid Arthritis - 15th International Congress of Rheu­ Di Martino. MJ. and Walz. D.T.: Effect of auranofin on anti­ matology. Paris. p. 25 (1981). body-dependent cellular cytotoxicity (AOCC) mediated by rat Ciompi. L.: Barbieri. P.: Mazzoni. M.R.: Robecchi. G.A. and Pas­ peripheral blood polymorphonuclear leukocytes and mono­ ero. G.: Evaluation of the clinical efficacy and tolerability of nuclear cells. Inflammation 4: 279-288 (1980). a new gold salt (auranofin) active by mouth in rheumatoid Di Martino. MJ. and Walz. D.T.: Inhibition of lysosomal en­ arthritis: in Capell et al. (Eds) International Symposium on zyme release from rat leukocytes by auranofin. Inflammation Auranofin. pp. 350-357 (Excerpta Medica. Amsterdam 1983). 2: 131-142 (1977). Coughlin. RJ.: Richter. M.B. and Panayi. G.S.: Changes in Di Martino. MJ.: Walz. D.T.: Wolff. CE. and Mann. W.A.: In­ mononuclear cell function in patients with rheumatoid arth­ hibition of lysosomal enzyme release from rat leukocytes by ritis following treatment with auranofin: in Capell et al. (Eds) a new gold compound - SK&F D-39162. Federation Pro­ International Symposium on Auranofin. pp. 71-80 (Excerpta ceedings 33: 558 (1974). Medica. Amsterdam 1983). Edelman. J.: Davis. P. and Owen. E.T.: Prevalence of oesino­ Crooke. S.T. and Mirabelli. CK.: Molecular mechanisms of ac­ philia during gold therapy for rheumatoid arthritis. Journal tion of auranofin and other gold complexes as related to their of Rheumatology 10: 121-123 (1983). biological activities. American 10urnal of Medicine 75 (Suppl. Ehrlich. G.E.: Freed. R.F. and Revach. M.R.: Aspects of safety. 6A) 109-113 (1983). efficacy and administration of auranofin. IX European Con­ Davies. J.: Bacon. P.A.: Hall. N.D. and Ring. E.FJ.: Placebo­ gress of Rheumatology. p. 79. Wiesbaden. Sept 2-8 (1979). controlled comparison of auranofin with Myocrisin in patients Empire Rheumatism Council: Gold therapy in rheumatoid arth­ with rheumatoid arthritis: in Capell et al. (Eds) International ritis: Report of a multi-centre controlled trial. Annals of the Symposium on Auranofin. pp. 194-200 (Excerpta Medica. Rheumatic Diseases 19: 95-119 (1960). Amsterdam 1983). Exton-Smith. A.N.: Millard. P.H.: Payne. P.R. and Wheeler. E.F.: Davis. P.: Action of gold compounds in vivo and in vitro on Method for measuring quantity of bone. Lancet 2: 1153-1154 immune responses: in Schattenkirchner. M. and Muller. W. (1969). (Eds) Rheumatology: An Annual Review. Vol. 8. pp. 75-83. Fam. A.G.: Paton: T.W.: Shamess. CJ. and Lewis. AJ.: Fulmi­ International Gold Workshop. Munich. Jan 14-15. 1982 (Kar­ nant colitis complicating gold therapy. Journal of Rheuma­ ger. Basel 1983). tology 7: 479-485 (1980). Auranofin: A Preliminary Review 418

Felix-Davies. D.O.: Delamere. J.P.: Bateman. J.R.: Gozzard. A.: (jhadially. F.N.: The aurosome. Journal of Rheumatology 6 (Supp\. Mace. A. and Wilkinson. J.R.: A 12-month trial of aura no fin 5): 45-50 (1979). versus D-penicillamine in rheumatoid arthritis. Annals of the (jl1o/lan. R.: Arlet. J.: Camus. J.P.: Deshayes. P.: Kahn. M.F.: Rheumatic Diseases 41: 640-641 (1982). Loyau. G.: Serratri,e. G.: Villiaumey. J. and Zeigler. G.: Aur­ Felix-Davies. D.O.: Stewart. A.M.: Wilkinson. B.R.: Bateman. J.R. anofin in the treatment of rheumatoid arthritis: A French and Delamere. J.R.: A 12-month comparative trial of aur­ multicentre open study: in Capell et a\. (Eds) International anofin and D-penicillamine in rheumatoid arthritis. Ameri­ S~mposium on Auranofin. pp. 81-96 (Excerpta Medica. Am­ can Journal of Medicine 75 (Supp\. 6A): 138-141 (1983). sterdam 1'183). Finkelstein. A.E.: Burrone. O.R.: Walz. D.T. and Misher. A.: Ef­ Giannini. E.G.: Brewer Jr. EJ. and Person. D.A.: Auranofin in lect of auranofin on DNA and protein synthesis in human the treatment of juvenile rheumatoid arthritis. Journal of lymphocytes. Journal of Rheumatology 4: 245-251 (1977a).· Paediatrics 102: 138-141 (l983a). Finkelstein. A.E.: Roisman. F.R. and De Titto. E.: Selective ac­ Giannini. E.H.: Person. D.A.: Brewer. EJ. and Parks. D.B.: Blood tion of auranofin on reactive immunoglobulin synthesis in and serum concentrations of gold after a single dose of aur­ rheumatoid arthritis. IX European Congress of Rheumatol­ anolin in children with juvenile rheumatoid arthritis. Journal ogy: III (Wiesbaden. Sept 2-8. 1979). of Rheumatology 10: 496-498 (l983b). Finkelstein. A.E.: Roisman. F.R.: Batista. V.: De Nudelman. F.G.: Gilliland. B.C and Mannick. M.: Rheumatoid arthritis; in Issel­ Dc Titto. E.H.: Mizraji. M. and Walz. D.T.: Oral chrysoth­ bacher et a\. (Eds) Principles of Internal Medicine. pp. 1872- erapy in rheumatoid arthritis: Minimum effective dose. Jour­ 1879 (McGraw Hill. New York 1980). nal of Rheumatology 7: 160-168 (1980). Gofton. J.P. and O·Brien. W.M.: Effects of auranofin on the Finkelstein. A.E.: Roisman. F.R.: Ladizesky. M.G. and Walz. D.T.: radiological progress of joint erosion in rheumatoid arthritis. -\uranolin and lysosomal enzymes. Journal of Rheumatology Journal of Rheumatology 9 (Supp\. 8): 169-172 (1982). 'I (Supp\. 8): 46-53 (1982a). Gofton. J.P. and O'Brien. W.: Roentgenographic findings during Finkelstein. A.E.: Roisman. F.R. and Manni. J.A.: Effect of aur­ auranofin treatment. American Journal of Medicine 75 (Supp\. anolin on antibody dependent cellular cytotoxicity in I'ilro 6A): (1983). and in rheumatoid arthritis patients. Arthritis and Rheuma­ Golion. J.P.: O'Brien. W.M.: Hurley. J.N. and Schemer, B.: X­ tism 25 (Supp\.): SI36 (1982b). ray evaluation of erosion progression in rheumatoid arthritis: Finkelstein. A.E.: Roisman. F.R. and Walz. D.T.: Effect of aur­ Double-blind study of auranofin versus placebo. X European anolin. a new antiarthritic agent. on immune complex-in­ Congress of Rheumatology. p. 9 Moscow, June 28 (1983). duced release of lysosomal enzymes from human leukocytes. Goldman. A.E. and McDonald, S.S.: Practices, strategies, and Inflammation 2: 143-150 (\ 977b). motivations in treatment of rheumatoid arthritis. American Finkelstein.-\.E.: Walz. D.T.: Batista. V.: Mizraji. M.: Roisman. Journal of Medicine 75 (Supp\. 6A): 79-85 (1983). F. and Misher. A.: Auranofin: New oral gold compound for Goobar. J.E. and Horton. J.: A one-year open clinical trial of treatment of rheumatoid arthritis. Annals of the Rheumatic auranofin in rheumatoid arthritis: in Capell et a\. (Eds) Inter­ Diseases 35: 251-257 (1976). national Symposium on Auranofin, pp. 328-338 (Excerpta Franchimont. P.: Hauwaert. C and Marchetti. M.: Auranofin and Medica. Amsterdam 1983). D-penicillamine: A comparative assessment of safety and ef­ Gottlieb. N.L.: Chrysotherapy. Bulletin on the Rheumatic Dis­ licac~ in patients with rheumatoid arthritis: in Capell et a\. eases 27: 912-917 (1977). (Eds) International Symposium on Auranofin. pp. 228-239 Gottlieb. N.L.: Comparative metabolism, efficacy and toxicity of (Excerpta Medica. Amsterdam 1983). oral and parenteral gold compounds. Rheumatologie 32: 245- Furst. D.E.: Personal communication (1983). 246 (1980). Furst. D.E.: Landaw. E.M.: Dromgoole. S.H.: Blocka. K. and Pau­ (jottlieb. N.L.: Comparative pharmacokinetics of parenteral and lus. H.E.: Pharmacokinetics of aura no fin after single and mul­ oral gold compounds. Journal of Rheumatology 9 (Supp\. 8): tiple dosing. Clinical Pharmacology and Therapeutics 31: 227- '1'1-10'1 (1982). 228 (1982). (jottlieb. N.L.: Comparative pharmacokinetics of stable oral and Genant. H.E.: Methods of assessing radiographic change in rheu­ parenteral gold compounds: in Schattenkirchner. M. and matoid arthritis. American Journal of Medicine 75 (Supp\. Muller. W. (Eds) Rheumatology: An Annual Review. Vo\. 8, 6A): 35-47 (1983). pp. 32-3'1. International Gold Workshop. Munich, Jan 14-15, (jerber. R.C.: Paulus. H.E.: Bluestone. R. and Lederer. M.: Ki­ 1982 (Karger. Basel 1983). netics of aurothiomalate in serum and synovial fluid. Arth­ Gottlieb. N. L.: Gold excretion and retention during auranofin ritis and Rheumatism 15: 625-629 (1972). treatment: A preliminary report. Journal of Rheumatology 6 Gerber. R.C.: Paulus. H.E.: Jennrich. R.I.: Lederer. M.: Blue­ (Supp\. ;): 61-07 (1979a). stone. R.: Bland. W.H. and Pearson. CM.: Gold kinetics fol­ (jottlil'b. N.L.: Metabolism and distribution of gold compounds. lowing aurothiomalate therapy: Usc of a whole body radia­ .iournal of Rheumatology 6 (Supp\. 5): 2-6 (l979b). tion counter. Journal of Laboratory and Clinical Medicine 83: (;ottlieb. N.L.: Sustained efficacy and safety of oral gold (aur­ 778-789 (1974). (wolin) in rheumatoid arthritis. Auranofin in Rheumatoid Auranofin: A Preliminary Review 419

'.rthritis - 15th International Congress of Rheumatology. Paris. substances on two types of inflammatory reactions in ani­ p. 5 (IYSI). mals. General Pharmacology 14: 419-427 (1983). Gottlieh. N.L. and Gray. R.G.: Pharmacokinetics of gold in rheu­ Heuer. M.A. and Morris. R.W.: Smith. Kline and French world­ matoid arthritis. Agents and Actions (SuppL 8): 529-538 (1980). wide clinical experience with auranofin: A review: in Capell Ciottlieh. N.L.: Smith. P.M. and Smith. E.M.: Pharmacodynamics et aL (Eds) International Symposium on Auranofin. pp. 474- of ''''Au and ""Au labeled aurothiomalate in blood. Arthritis 503 (Exeerpta Medica. Amsterdam 1983). and Rheumatism 17: 171-183 (1974). Heuer. M.A.: Morris. R.W.: Pietrusko. R.G. and Schemer, B.1.: Gottlieh. N.L.: Riskin, W.: Maken. C: Goldberg. E. and Smith. Experience with auranofin therapy: A review of worldwide P.M.: A clinical-metabolic study of auranofin in rheumatoid data. X European Congress of Rheumatology. p. 6 Moscow. arthritis. Clinical Research 28: 146,1. (1980a). June ~8 (1983). Gottlieb. N.L.: Riskin. W.: Maken. C: Goldberg. E. and Smith. Homma. M.: Abe. T.: Akizuki. M.: Shiokawa, Y.: Shichikawa, P.M.: Extended experience with auranofin in rheumatoid K.: Kageyama. T.: Yoshizawa. H.: Azuma. T.: Mizushima. Y.: arthritis. Arthritis and Rheumatism 23: 684 (1980b). Okazaki. T. and Sugawara. S.: Interim results of a multicenter Hafstrom. I.: Auranofin (SK&F D-39162) in the treatment of open study with auranofin in Japan. Journal of Rheumatol­ rheumatoid arthritis. Clinical Trials Journal 20: 25-35 (1983). ogy 9 (SuppL 8): 160-168 (1982). Hafstrbm. I.: Palmblad. J. and Uden. A.-M.: Modulation of neu­ Hunt. B.P. and Holt. P.1.L.: Oral gold therapy in rheumatoid trophil functions by auranofin. Scandinavian Journal of arthritis. Auranofin in Rheumatoid Arthritis - 15th Inter­ Rheumatology 45 (SuppL): 14 (1982). national Congress of Rheumatology, p. 49-50. Paris. Jun 21- Hafstrom. I.: Ringertz. B.: Uden. A. and Palmblad. J.: Auranofin ~7 (1981). modulates immune functions: in Capell et aL (Eds) Interna­ Hunt. B.P. and Holt. P.J.L.: Oral gold therapy in rheumatoid tional Symposium on Auranofin. pp. 382-388 (Exeerpta Med­ arthritis: in Capell et aL (Eds) International Symposium on ica. Amsterdam 1983a). Auranofin. pp. 292-302 (Excerpta Medica. Amsterdam 1983). Hafstrom. I.: Udcn. A.-M. and Palmblad. J.: Modulation of neu­ Iannuzzi. L.: Dawson. N.: Zein. N. and Kushner. I.: Does drug trophil functions by auranofin. Scandinavian Journal of therapy slow radiographic deterioration in rheumatoid arth­ Rheumatology 12: 97-105 (l983b). ritis" New England Journal of Medicine 309: 1023-\028 (1983). Hanna. N.: Di Martino. M.: Griswold. D.E. and Poste. G.: Im­ Intocna. A.P.: Flanagan. T.L.: Walz. D.T.: Gutzai!. L.: Swagzdis. munology of auranofin - An overview: in Capell et aL (Eds) .I.E.: Flagiello Jr. .I.: Hwang. B.Y.-H.: Dewey. R.H. and No­ International Symposium on Auranofin. pp. 60-70 (Excerpta guchi. H.: Pharmacokinetics of auranofin in animals. Journal Medica. Amsterdam 1983). of Rheumatology 9 (Supp!. 8): 90-98 (1982). Harris. E.F.: Morrow. R.L. and Measel. J.W.: The effect of gold .Iarner. D.: Ammitzbol!. F.: Sinding. J. and Thygesen. H.M.: Aur­ on the '" rilm activity of human natural killer cells. American anntin and Myocrisin (gold sodium thiomalate): A doub\c­ Society for Microbiology - 83rd Annual Meeting. New Or­ hlind comparative study: in Capell et a!. (Eds) International leans. p. 96 (1983). S, mposium on Auranofin. pp. 358-365 (Excerpta Medica. Harth. M.: Gold and modulation of the immune response. Jour­ '.msterdam 1983) . nal of Rheumatology 6 (SuppL 5): 7-11 (1979). .Iarner. D. and Nielsen. A.M.: Auranofin (SK + F 39162) induced Harth. M.: Personal communication (1983). enterocolitis in rheumatoid arthritis. Scandanavian Journal of Harth. M.: Modulation of immune responses by gold salts. Agents Rheumatology 12: 254-256 (1983) . and Actions (SuppL 8): 465-476 (1980). .Idlum. E.: Munthe. E.: Guida!. G. and Aaseth. J.: Gold and thiol Herrlinger. J.D.: Difference in the pharmacokinetics. protein compounds in the treatment of rheumatoid arthritis: Excre­ binding and cellular distribution of gold when different com­ tory fale and·t·issue distribution of thiomalate in relation to pounds arc used: in Schattenkirchner. M. and Muller. W. (Eds) gold alier administration of aurothiomalate. Scandinavian Rheumatology: An Annual Review. Vol. 8. pp. 52-57. Inter­ Journal of Rheumatology (Supp!. 28): 28-36 (1979). national Gold Workshop. Munich. Jan 14-15. 1982 (Karger. Jessop. J.D.: Gold in the treatment of rheumatoid arthritis - Why, Basel 1983). when. and how" Journal of Rheumatology 6 (Supp!. 5): 12- Herrlinger. J.D.: Alsen. C: Beress. R.: Hecker. U. and Weikert. 17 (I Y79). W.: Distribution of gold in serum erythrocytes and white blood .Iessop . .I.D. and Johns. R.G.S.: Serum gold determinations in cells alier /11 rilm incubation and during chrysotherapy with patients with rheumatoid arthritis receiving sodium auro­ different gold compounds. Journal of Rheumatology 9 (Supp!. thiomalate. Annals of the Rheumatic Diseases 32: 228-232 8) SI-8Y (198~). ( 1973). Herrlinger. J.D.: Alsen. C: Beress. R.: Hecker. U. and Seiler. K.U.: JcWJp . .I.D.: Wilkins. M. and Young. M.H.: The effect of anti­ Distrihution of gold inside and outside the cells of blood dur­ rheumatic drugs on the phagocytic activity of synovial mac­ ing treatment with different gold compounds: in Auranofin rophages in organ culture. Annals of the Rheumatic Diseases in Rheumatoid Arthritis 15th International Congress of 41: 6J~-6JJ (1982). Rheumatologists. Paris. Jun 21-27. p. 41 (1981). Kaik. B.: Brol!. H.: Muller-Fassbender. H.: Rau. R.: Schattenkir­ Hert/. F .. CheHier. M.M.: and Defeudis. F.V.: Effects of various chner. M. and Zeidler. H.: Auranofin and Tauredon in the Auranofin: A Preliminary Review 420

treatment of chronic polyarthritis: in Capell et al. (Eds) Inter­ Larsen. A.: Problems in the radiological assessment of bone and national Symposium on Auranofin, pp. 453-463 (Excerpta joint changes in patients with rheumatoid arthritis; in Schat­ Medica. Amsterdam 1983). ten kirchner. M. and Muller, W. (Eds) Rheumatology: An An­ Kaplan. H.: Auranofin: Bane or bonanza for the nonrheumatol­ nual Review, Vol. 8, pp 197-203. International Gold Work­ ogist. American Journal of Medicine 75 (Suppl. 6A): 145-151 shop. Munich, Jan 14-15, 1982 (Karger, Basel 1983). (1983). Larsen. A.: Dale. M. and Eek, M.: Radiographic evaluation of Katz. W.A.: Alexander. S.: Bland, J.H.: Blechman, W.; Bluhm, rheumatoid arthritis and related conditions by standard ref­ G.B.: Bonebrake, R.A.; Falbo, A.; Greenwald, R.A.: Hartman, erence films. Acta Radiologica 18: 481-491 (1977). S.: Hobbs. T.: Indenbaum, S.; Lergier, J.E.; Lanier, B.G.; Larsen. A.: Horton, J. and Osborne, c.: Auranofin compared with Lightfoot Jr, R.W.; Phelps, P.; Sheon, R.P.; Toretti, D.; Wen­ intramuscular gold in the long-term treatment of rheumatoid ger. M.E. and Wilske, K.: The efficacy and safety of auranofin arthritis: An x-ray analysis; in Capell et al. (Eds) International compared to placebo in rheumatoid arthritis. Journal of Symposium on Auranofin, pp. 264-277 (Excerpta Medica, Rheumatology 9 (Suppl. 8): 173-178 (1983). Amsterdam 1983). Kaye. R.L.: The current clinical status of gold therapy in rheu­ Lee. I.-J.: Chrysotherapy for rheumatoid arthritis. New Medical matic diseases. Journal of Rheumatology 9 (Suppl. 8): 124- Journal 24: 123-129 (1981). 131 (1982). Lewis, AJ.; Cottrey, J.; White, D.D.; Fox, P.K.; McNeillie, A.; Keegan. D.AJ.: Cole, D.S.; Hodkinson, E. and Podmore, P.: A Dunlop, J.; Smith, W.E. and Brown, D.H.: Action of gold comparative open study of the efficacy and safety of gold sod­ salts in some inflammatory and immunological models. Ag,:nts ium thiomalate and auranofin treatment in patients with and Actions 10: 63-77 (1980). rheumatoid arthritis; in Capell et al. (Eds) International Sym­ Lewis, D. and Capell, H.A.: Is auranofin preferable to gold sod­ posium on Auranofin, pp. 430-441 (Excerpta Medica, Am­ ium thiomalate in the management of rheumatoid arthritis?, sterdam 1983). in Capell et al. (Eds) International Symposium on Auranofin, Khan. M.F.; Doury, P.; Delcambre, B.; Desproges-Gotteron, R.; pp. 147-155 (Excerpta Medica, Amsterdam 1983). Gougeon. J.; Kuntz, D.; D'Eshougues, J.R.; Roux, H. and Sany, Lewis, AJ. and Walz, D.T.: Immunopharmacology of gold; in J.: A multicentre double-blind comparative study of auran­ Ellis, G.P. and West, G.B. (Eds) Progress in Medicinal Chem­ ofin and intramuscular gold (Allochrysine); in Capell et al. istry 19: 2-58 (Elsevier Biomedical Press, 1982). (Eds) International Symposium on Auranofin, pp. 165-180 Lewis, D.; Capell, H.A.; McNeil, CJ.; Iqbal, M.S.; Brown, D.H. (Excerpta Medica, Amsterdam 1983). and Smith, W.E.: Gold levels produced by treatment with Kleine. L.: Effect of three different gold compounds on the func­ auranofin and sodium aurothiomalate. Annals of the Rheu­ tions of human blood monocytes in I'ilro; in Schatten Kir­ matic Diseases 42: 566-570 (1983). chner, M. and Muller, W. (Eds) Rheumatology: An Annual Lewis, D.: McNeil, c.; Smith, W.E. and Capell, H.A.: A placebo­ Review. Vol. 8, pp. 58-62. International Gold Workshop, controlled clinical and laboratory comparison of auranofin Munich. Jan 14-15, 1982 (Karger, Basel 1983). and Myocrisin in patients with rheumatoid arthritis. Annals Kleine. L.: Buckendorf, K. and Herrlinger, J.D.: The influence of of the Rheumatic Diseases 41: 309 (1982). nonsteroidal antiinflammatory drugs and gold salts on human Lipsky. P.E.: Remission-inducing therapy in rheumatoid arthritis. monocyte function in l'ilro. Auranofin in Rheumatoid Arth­ Infectious Disease 13: 4-passim (1983). ritis. p.75-77. 15th International Congress of Rheumatology, Lipsky, P.E. and Ziff, M.: Inhibition of antigen and mitogen in­ Paris. Jun 21-27 (1981). duced human lymphocyte proliferation by gold compounds. Kobayashi. K.: Sato, H.; Sekine, F.; Ohno, I.; Ohseto, Y.; Hamai, Journal of Clinical Investigation 59: 455-466 (1977). T.: Negishi. M. and Takahashi, T.: Generation of human peri­ Lorber. A.: Effects of chrysotherapy on cell-mediated immune re­ pheral blood suppressor cell activity by auranofin. Arerugi 31: sponse. Clinical Pharmacology and Therapeutics 31: 245 948-955 (1982). (1982). Komatsubara, Y.: Shichkawa, K.: Magaya, I. and Yamamoto, S.: Lorber. A.: Auranofin effects on cytotoxicity. Journal of Rheu­ Results of a controlled comparative study of auranofinand matology 10: 517 (l983a). injectable gold in rheumatoid arthritis, abstracts from the 5th Lorber, A.: Personal communication (l983b). SEA PAL Congress of Rheumatology, Bangkok, Jan 26 (1984). Lorber. A.: Experience and rationale of monitoring plasma levels Ladizesky. M.G.: Roisman, F.R.; Walz, D.T. and Finkelstein, A.E.: of gold in rheumatoid arthritis. Agents and Actions 8 (Suppl.): Auranofin inhibition of dextran induced release of iJ-glucu­ 539-573 (1980). ronidase in adjuvant-induced arthritis in rats. IX European Lorber. A.: Atkins, CJ.; Chang, c.c.; Lee, Y.B.; Starrs, J. and Congress of Rheumatology. Wiesbaden, Sept 2-8, p. 79 (1979). Bovy. R.A.: Monitoring serum gold values to improve chry­ Lamprecht. S.T.: Finkelstein, A.E.; Walz, D.T.: Schwartz. B. and sotherapy in rheumatoid arthritis. Annals of the Rheumatic Krawiec. J.: Inhibition of PGE,-stimulation of cyclic AMP Diseases 32: 133-139 (1973). formation by auranofin. Auranofin in Rheumatoid Arthritis Lorber. A.: Cohen, R.L.; Chang, c.c. and Anderson, H.E.: Gold - 15th International Congress of Rheumatology, Paris, Jun determinations in biological fluids by atomic absorption spec­ 21-27. pp. 85-89 (1981). trophotometry: Application to chrysotherapy in rheumatoid Auranofin: A Preliminary Review 421

arthritis patients. Arthritis and Rheumatism II: 170-177 drugs. Annals of the Royal College of Physicians and Sur­ ( 1968). geons of Canada 16: 394 (1983). Lorber. A.: Jackson. W.H. and Simon, T.M.: Assessment of im­ Mirabelli, e.K. and Crooke, S.T.: Pharmacology of auranofin - mune response during chrysotherapy, comparison of gold A review and future perspective; in Capell et al. (Eds) Inter­ sodium thiomalate 1'5 auranofin. Scandinavian Journal of national Symposium on Auranofin, pp. 17-31 (Excerpta Med­ Rheumatology 10: 129-137 (1981). ica, Amsterdam 1983). Lorber. A.: Jackson, W.H. and Simon, T.M.: Effects of chrysoth­ Moon, M.S.: Kim, I.; Ok, I.Y.: Rhee, S.K. and Yeom, G.S.: Chty­ erapy on cell mediated immune response. Journal of Rheu­ sotherapy for the treatment of rheumatoid arthritis. Auran­ matology 9 (Suppl. 8): 37-45 (1982). ofin in Rheumatoid Arthritis, 15th International Congress of Lorber. A.: Kunishima, D.H.: Harralson, A.F. and Simon, TM.: Rheumatology p. 9 (Paris, 1981). II. Unbound versus total serum gold concentration: Pharma­ Morteo. O.G.: Cocco, J.A,M.; Marcos, J.e. and Arturi, A.S.: Es­ cological actions on cellular function. Journal of Rheumatol­ tudio de la eficacia y tolerancia de auranofin en eltratamiento ogy 10: 568-573 (1983a). de la artritis reumatoidea. Prensa Medica Argentina 70: 380- Lorber, A.: Simon, T.M.: Leeb, J.: Peter, A. and Wilcox, S.A.: 382 (1983). Effect of chrysotherapy on parameters of immune response. Muller-Fassbender, H.: Problems in the radiological assessment Journal of Rheumatology 6 (Suppl. 5): 82-90 (1979a). of bone and joint changes in patients with rheumatoid arth­ Lorber. A.: Vibert GJ.: Harralson, A.F. and Simon, T.M.: Un­ ritis: in Schattenkirchner, M. and Muller, W. (Eds) Rheu­ bound serum gold: Procedure for quantitation. Journal of matology: An Annual Review, Vol. 8, pp. 209-2 I I. Interna­ Rheumatology 10: 563-567 (l983b). tional Gold Workshop, Munich, Jan 14-15, 1982 (Karger, Basel Lorber. A.: Wilcox, S.A.: Vibert, GJ.: and Simon, TM.: Carbon 1983). rod atomization analysis: Application to in vivo lymphocyte Muller-Fassbender, H.: Kaik, D.: Rau, R.; Schattenkirchner, M. gold quantitation. Journal of Rheumatology 6 (Suppl. 5): 31- and Zeidler, H.: Controlled double-blind comparative study 39 (1979b). of auranofin and aurothiomalat. Aktuelle Rheumatologie 8 Marcolongo, R.: Lalumera, M.: Calabria, A.: Gerli, R.: Alessan­ (Suppl. I): 40-43 (1983). drini. e. and Robecchi, G.: Effects of auranofin and other Nathan, I.; Finkelstein, A.E.; Walz, D.T and Dvilansky, A.: Stud­ gold salts on polymorphonuclear neutrophil functions; in Ca­ ies of the effect of auranofin, a new antiarthritic agent, on pell et al. (Eds) International Symposium on Auranofin, pp. platelet aggregation. Inflammation 6: 79-85 (1982). 408-427 (Excerpta Medica, Amsterdam 1983). Noguera, E.; Mulero, J.: Larrea, A.; Cruz, J.; Gijon, J.; Perez­ Mascarenhas, B.R.: Granda, J.L. and Freyberg, R.H.: Gold me­ Ayala, e.; Fernandez-Yanez, I. and Martinez, A.: A multi­ tabolism in patients with rheumatoid arthritis treated with centre open study of auranofin from Spain; in Capell et al. gold compounds - reinvestigated. Arthritis and Rheumatism (Eds) International Symposium on Auranofin, pp. 366-379 15: 391-402 (1972). (Excerpta Medica, Amsterdam 1983). Mason. R.W.: Sharma, R.P. and McQueen, E.G.: Pharmacokin­ O'Brien. W.M.: The effects of auranofin on the rate of radiologic etics and subcellular interactions of gold complexes: Signifi­ erosion in rheumatoid arthritis. Auranofin in Rheumatoid cance in relation to therapeutic and side effects. Agents and Arthritis - 15th International Congress of Rheumatology, p. Actions 8 (Suppl.): 489-507 (1980). 21. Paris, Jun 21-27 (1981). Menard. H.A.: Beaudet, F.: Davis, P.: Harth, M.: Percy, J.S.: Rus­ O'Duffy, J.D.: Gold compounds in rheumatoid arthritis. Drug sell. A.s. and Thompson, J.M.: Gold therapy in rheumatoid Therapy 4: 54-66 (1979). arthritis: Interim report of the Canadian Multicenter Pro­ Palmer. D.G.: Highton, H.: MacKinnon, M.: Myers, D.B. and spective Trial comparing sodium aurothiomalate and aur­ Sharma. R.: A double-blind parallel trial of auranofin and anofin. Journal of Rheumatology 9 (Suppl. 8): 179-183 (1982). placebo in rheumatoid arthritis with evidence for compati­ Menninger. H. and Burkhardt H.: Effect of gold compounds on bility with certain non-steroidal anti-inflammatory drugs; in the activity of lysosomal enzymes: in Schattenkirchner, M. Capell et al. (Eds) International Symposium on Auranofin, and Muller. W. (Eds) Rheumatology: An Annual Review, Vol. pp. 313-327 (Excerpta Medica, Amsterdam 1983). 8. pp. 84-98. International Gold Workshop, Munich, Jan 14- Parke. A.L.: Black, e.M. and Hughes, G.R.V.: A double-blind 15. 1982 (Karger, Basel 1983a). study comparing Myocrisin and auranofin in patients with Menninger. H. and Burkhardt, H.: Pharmakologische Fragen des rheumatoid arthritis previously controlled by Myocrisin; in Klinikers an Auranofin. Aktuelle Rheumatologie 8 (Suppl. I): Capell et al. (Eds) International Symposium on Auranofin, 9-13 (1983b). pp. 464-471 (Exeerpta Medica. Amsterdam 1983). Meyers. o.L.: Experience with an oral gold formulation for the Payne. 8J.: The comparative toxicity of gold salts. Journal of treatment of rheumatoid arthritis. IX European Congress of Rheumatology 9 (Suppl. 8): 79-80 (1982). Rheumatology, Wiesbaden. Sept 3-8, p. 161 (1979). I'a\nc. 8J. and Arena. E.: The subacute and chronic toxicity of Minta. J.: Williams. D.: Urowitz, M.B. and Sm¥the, H.A.: On the SK&F 36914. SK&F D-39162. and gold sodium thiomalate mechanism of inhibition of superoxide anion production in in rats. Veterinary Pathology 15 (Suppl. 5): 13-22 (1978a). human polymorphonuclear-leukocytes by anti-rheumatic Payne. 8..1. and Arena. E.: The subacute and chronic toxicity of Auranofin: A Preliminary Review 422

SK&F 36914 and SK&F D-39162 in dogs. Veterinary Path­ Medica. Amsterdam 1983). ology 15 (Suppl. 5): 9-12 (l978b). Schattenkirchner. M. and Delattre. M.: Efficacy and safety of aur­ Payne. B.J. and Saunders. L.Z.: Heavy metal nephropathy of ro­ anofin: A European multicentre trial. X European Congress dents. Veterinary Pathology 15 (Suppl. 5): 51-87 (1978). of Rheumatology. p. 5. Moscow. June 28 (1983). Pedersen. S.M. and Graabaek. P.M.: Gold in erythrocytes. whole Schattenkirchner. M.: Kaik. B.: Miiller-Fassbender, H.: Rau. R. blood. and plasma during long-term chrysotherapy. Annals of and Zeidler. H.: Auranofin and sodium aurothiomalate in the the Rheumatic Diseases 39: 576-579 (1980). treatment of rheumatoid arthritis. Journal of Rheumatology Plaza. J.J.: Herrero. G.: Barat. A.: Lomtaif. J.1.: Hernando. L.: 9 (Suppl. 8): 184-189 (1982). Vallado. P. and Oliva. H.: Membranous glomerulonephritis Scheinberg. M.A.: Finkelstein. A.E. and Walz. D.T.: Oral chry­ as a complication of oral gold therapy. Annals of Internal sotherapy: Effect on neutrophil and monocyte chemotaxis. IX Medicine 97: 563-564 (1982). European Congress of Rheumatology. Wiesbaden. Sept 2-8. Prouse. P.1. and Gumpel, J.M.: Placebo-controlled comparison p. 53 (1979). of auranofin with gold sodium thiomalate: in Capell et al. Scheinberg. M.A.: Santos. L. and Finkelstein. A.: Gold inhibition (Eds) International Symposium on Auranofin, pp. 303-312 of human monocyte function. Arthritis and Rheumatism 24: (Excerpta Medica, Amsterdam 1983). SI17 (1981). Prouse. P.1.: Gumpel, J.M.: Howard, A. and Ward, R.1.: Double­ Schorn. D.: An open clinical study with auranofin in rheumatoid blind controlled comparison of auranofin. gold sodium arthritis: 2 year follow-up: in Capell et al. (Eds) International thiomalate. or placebo: in Auranofin in Rheumatoid Arthri­ Symposium on Auranofin. pp. 339-344 (Excerpta Medica. tis. pp. 7-12. 15th International Congress of Rheumatology. Amsterdam 1983). Paris. June 21-27 (1981). Schorn. D.: An oral gold formulation in rheumatoid arthritis. South Rau. R.: Kaik, B.: Miiller-Fassbender. H.: Schattenkirchner. M. African Medical Journal 62: 313-316 (1982). and Zeidler. H.: Auranofin (SK&F 39162) and sodium auro­ Schorn. D.: Osteoporosis in the rheumatid hand - The effects of thiomalate in the treatment of rheumatoid arthritis: in Schat­ treatment with D-penicillamine and oral gold salts. South Af­ ten kirchner, M. and Miiller, W. (Eds) Rheumatology: An An­ rican Medical Journal 63: 121-123 (1983). nual Review. Vol. 8, pp. 162-174. International Gold Scott. J. and Huskisson, E.e.: Comparative study of auranofin in Workshop. Munich. Jan 14-15, 1982 (Karger. Basel 1983). rheumatoid arthritis. Auranofin in Rheumatoid Arthritis. 15th Revach. M.: Freed. R.L. and Ehrlich, G.E.: Reversible proteinuria International Congress of Rheumatology, Paris. Jun 21-27. p. as a complication of oral gold therapy. Arthritis and Rheu­ 5-6 (1981). matism 22: 1417-1418 (1979). Shaw. e.F. (III): The biochemistry and subcellular distribution Roisman. F.R.: Walz. D.T. and Finkelstein, A.E.: Inhibitory ac­ of gold in kidney tissue: Implications for chrysotherapy and tion of auranofin on superoxide production by phagocytic cells nephrotoxicity. Agents and Actions 8 (Suppl.): 509-528 (1980). and blockade of the inhibition by thiol protecting agents. Sigler. J.W.: Parenteral gold in the treatment of rheumatoid arth­ Arthritis and Rheumatism 25: S 130 (1982). ritis. American Journal of Medicine 75 (Suppl. 6A): 59-62 Rubenstein. H.M. and Dietz. A.A.: Serum gold. II. Levels in rheu­ (1983). matoid arthritis. Annals of the Rheumatic Diseases 32: 128- Simon. T.M.: Kunishima. D.H.: Hoeschele. J.D. and Lorber. A.: 132 (1973). Inhibitory effects of aura no fin analogs on HeLa cells. In vitro Russell. A.S.: Davis. P. and Miller. e.: The effect of a new anti­ 19: 275 (1983). rheumatic drug, triethylphosphine gold (auranofin), on in I'itro Simon. T.M.: Kunishima. D.H.: Vibert. G.J. and Lorber. A.: Cell­ lymphocyte and monocyte cytotoxicity. Journal of Rheuma­ ular antiproliferative action exerted by auranofin. Journal of tology 9: 30-35 (1982). Rheumatology 6 (Suppl. 5): 91-97 (l979a). Salmeron. G. and Lipsky. P.E.: Effect of gold compounds on hu­ Simon. T.M.: Kunishima. D.H.: Vibert. G.1. and Lorber. A.: In­ man mononuclear phagocyte functions: in Schattenkirchner. hibitory effects of a new oral gold compound on HeLa cells. M. and Muller. W. (Eds) Rheumatology: An Annual Review, Cancer 44: 1965-1975 (I 979b ). Vol. 8. pp 63-74. International Gold Workshop, Munich, Jan Simon. T.M.: Kunishima. D.H.: Vibert. G.1. and Lorber. A.: 14-15. 1982 (Karger, Basel 1983). Screening trial with the coordinated gold compound auran­ Salmeron. G. and Lipsky, P.E.: Modulation of human immune ofin using mouse lymphocytic leukemia P388. Cancer Re­ responsiveness in I'itro by auranofin. Journal of Rheumatol­ search 41: 94-97 (1981). ogy 9 (Suppl. 8): 25-31 (1982). Sliwinski. A.1. and Guertin, M.A.: Gold suppression of human Sany. J.: Ariel. J.: Camus, J.T.: Delcambre, 8.: Desproges-Got­ neutrophil function in I'ilro. Biochemical Pharmacology 31: teron. R.: Deshayes. P. et al.: Interim results of two French 671-676 (1982). multicenter trials of auranofin: in Auranofin in Rheumatoid Smith. P.M.: Smith. E.M. and Gottlieb. N.L.: Gold distribution Arthritis. pp. 61-72. 15th International Congress of Rheu­ in whole blood during chrysotherapy. Journal of Laboratory matology. Paris, June 21-27 (1981). and Clinical Medicine 82: 930-937 (1973). Saunders. L.Z.: The toxicology of auranofin: in Capell et al. (Eds) Smith. P.R.: Brown. G.M.M. and Meyers. O.L.: A 96-week open International Symposium on Auranofin, pp. 45-59 (Excerpta comparative study of auranofin versus gold sodium thioma- Auranofin: A Preliminary Review 423

late in rheumatoid arthritis: in Capell et a!. (Eds) Interna­ Rheumatic Diseases 39: 31-36 (1980). tional Symposium on Auranofin, pp. 181-193 (Excerpta Med­ Van Riel. P.L.CM.: Gribnau, F.WJ.: Van de Putte, L.B.A. and ica. Amsterdam 1983). Yap. S.H.: Loose stools during auranofin treatment: Clinical Smith. P.R.: Brown. G.M.M. and Meyers, O.L.: An open com­ study and some pathogenetic possibilities. Journal of Rheu­ parative study of auranofin I'S gold sodium thiomalate. Jour­ matology 10: 222-226 (1983a). nal of Rheumatology 9 (Supp!. 8): 190-196 (1982). Van Riel. P.L.CM.: Van de Putte, L.B.A.: Gribnau, F.WJ. and Stein. H.B. and Urowitz, M.B.: Gold-induced enterocolitis. Case MacRae, K.D.: A single-blind comparative study of auranofin report and literature review. Journal of Rheumatology 3: 21- and aurothioglucose in patients with rheumatoid arthritis. 26 (1976). Pharmaceutisch Weekblad 5: 37 (l983b). Stote. R.M.: Blodgett R.C and Walz, D.T.: Pre-clinical experi­ Van Riel. P.L.CM.: Van de Putte, L.B.A.: Gribnau, F.WJ.: ence with auranofin. X European Congress of Rheumatology, MacRae, K.D. and de Rooy, DJ.A.M.: A single-blind com­ p. 2 Moscow, June 28 (1983). parative study of auranofin and gold thioglucose in patients Sutton. B.M.: Hempel. J.C and Hill, D.T.: Auranofin: Its chem­ with rheumatoid arthritis: in Capell et a!. (Eds) International ical development and unique molecular properties: in Capell Symposium on Auranofin, pp. 135-146 (Excerpta Medica, et a!. (Eds) International Symposium on Auranofin, pp. 6-16 Amsterdam 1983c). (Excerpta Medica, Amsterdam 1983). Vernon-Roberts, B.: Action of gold salts on the inflammatory re­ Szabo. K.T.: Di Febbo, M.E. and Phelan, D.G.: The effects of sponse and inflammatory cell function. Journal of Rheuma­ gold-containing compounds on pregnant rabbits and their fe­ tology 6 (Supp!. 5): 120-129 (1979). tuses. Veterinary Pathology 15 (Supp!. 5): 97-102 (l978a). Walz. D.T.: Auranofin: in Goldberg, M.E. (Ed.) Pharmacological Szabo. K.T.: Guerriero, EJ. and Kang, YJ.: The effects of gold­ and Biochemical Properties of Drug Substances, Vo!. 2, pp. containing compounds on pregnant rats and their fetuses. 400-406 (American Pharmaceutical Association, Washington Veterinary Pathology 15 (Supp!. 5): 89-96 (l978b). 1979). Tausch, G.: Teherani, D.K.: Altmann, H.: Broil, H.: Eberl, R. and Walz, D.T.: The role of gold compounds on the immune system: Topaloglou, A.: Concentration of gold in blood (total), eryth­ in Yamamura, Y. (Ed.) Immunomodulation by Microbial rocytes and chromatin of lymphocytes after therapy with auro­ Products and Related Synthetic Compounds, pp. 532-535 thiomalat and triethylphosphin-gold in patients with rheu­ (International Congress Series no. 563, 1981). matoid arthritis. Aktuelle Rheumatologie 8 (Supp!. I): 5-8 Walz, D.T.: Di Martino, MJ.: Chakrin, L.W.: Sutton, B.M. and ( 1983). Misher, A.: Antiarthritic properties and unique pharmacol­ The Cooperating Clinics Committee of the American Rheuma­ ogic profile of a potential chrysotherapeutic agent: SK&F D- tism Association: A controlled trial of gold salt therapy in 39162. Journal of Pharmacology and Experimental Thera­ rheumatoid arthritis. Arthritis and Rheumatism 16: 353-358 peutics 197: 142-152 (1976). ( 1973). Walz. D.T.: Di Martino, MJ. and Griswold, D.E.: Comparative Thompson. J.: Davis, P.: Harth, M.: Menard, H. and Rothwell, pharmacology and biological effects of different gold com­ RS: A prospective comparison of gold sodium thiomalate pounds. Journal of Rheumatology 9 (Suppl. 8): 54-60 (1982a). and auranofin in the treatment of rheumatoid arthritis: in Walz. D.T.: Di Martino, MJ. and Griswold, D.E.: Immuno­ Auranofin in Rheumatoid Arthritis, p. 73. 15th International pharmacology of auranofin and gold sodium thiomalate: Ef­ Congress of Rheumatology, Paris, June 21-27 (1981). fects on humoral immunity. Journal of Rheumatology 6 (Supp!. Thompson. J.: Harth, M.: Davis, P.: Menard, H. and Beaudet, 5): 74-81 (1979a). F.: A twenty-four month study of auranofin and gold thio­ Walz. D.T.: Di Martino, MJ. and Griswold, D.E.: Mechanisms malate in the treatment of rheumatoid arthritis. Annals of the of action of auranofin: Effects on humoral immune response. Royal College of Physicians and Surgeons of Canada 16: 389 Journal of Rheumatology 9 (Supp!. 8): 32-36 (I 982b). ( 1983). Walz. D.T. and Griswold, D.E.: Immunopharmacology of gold Trentham. D.E. and Masi, A.T.: Carpo-metacarpal ratio: A new sodium thiomalate and auranofin (SK&F D-39162). Effects quantitative measure of radiologic progression of wrist in­ on cell mediated immunity. Inflammation 3: 117-128 (1978). volvement in rheumatoid arthritis. Arthritis and Rheuma­ Walz. D.T.: Griswold, D.E.: Di Martino, MJ. and Bumbier, E.E.: tism 19: 939-944 (1976). Distribution of gold in blood following administration of aur­ Tumiati. B.: Terzi. C: Zini, R.: Baricchi, R. and Bellelli, A.: anolin (SK&F D-39162). Journal of Rheumatology 6 (Supp!. Felty's syndrome: Response to auranofin. Clinical and Ex­ 5): 56-60 (1979b). perimental Rheumatology I: 183-184 (1983). Walz. D.T.: Griswold, D.E.: Di Martino, MJ. and Bumbier, E.E.: T\cdc. N. and Strandberg, B.: The effect of auranofin compared Effect of auranofin dose regimen change upon cell-associated with Myocrisin in the treatment of rheumatoid arthritis: in gold in rheumatoid arthritic patients. Journal of Rheumatol­ Capell et al. (Eds) International Symposium on Auranofin, ogy 8: 829-832 (1981). pp. 442-452 (Excerpta Medica, Amsterdam 1983). Ward. RJ.: Cashmore, G.: Meswani, P.: GumpeL J.M. and Prouse, Van de Stadt R..I. and Abbo-Tilstra, B.: Gold binding to blood PJ.: Alterations of plasma copper and zinc in patients with cells and serum proteins during chrysotherapy. Annals of the rheumatoid arthritis treated with auranofin, gold sodium Auranofin: A Preliminary Review 424

thiomalate or placebo. Auranofin in Rheumatoid Arthritis, p. tology 7: 633-637 (1980). 79-82. 15th International Congress of Rheumatology, Paris, Weiss. T.E.: Auranofin: Dose related risk to benefit. American Jun 21-27 (1981). Journal of Medicine 75 (Suppl. 6A): 128-132 (1983). Ward. R.J.: Doshi, P.: Cashmore, G.: Howard, A.: Prouse, P.1. Wenger. M.E.: Alexander, S.: Bland, J.H. and Blechman, W.1.: and GumpeL J.M.: Clinical significance of trace metal alter­ Auranofin versus placebo in the treatment of rheumatoid ations in patients with rheumatoid arthritis receiving either arthritis. American Journal of Medicine 75 (Suppl. 6A): 123- Myocrisin or auranofin: in Capell et al. (Eds) International 127 (1983a). Symposium on Auranofin, pp. 389-397 (Excerpta Medica, Wenger. M.E.: Bernhard, G.C: Heller, M.D.: O'Brien, W.M.: Amsterdam 1983a). Reese, R.W.: Rosenthal, S.H.: Weiss, T.E. and Scheffler, B.1.: Ward, J.R.: Williams, H.1.: Boyce, E.: Egger, M.1.: Reading, J.C Therapy for rheumatoid arthritis: Transferring treatment from and Samuelson Jr, CO.: Comparison of auranofin, gold sod­ injectable gold to auranofin: in Capell et al. (Eds) Interna­ ium thiomalate, and placebo in the treatment of rheumatoid tional Symposium on Auranofin, pp. 201-210 (Excerpta Med­ arthritis: Subsets of responses. American Journal of Medicine ica, Amsterdam 1983b). 75 (Suppl. 6A): 133-137 (1983b). Wessell, J. and Davis, P.: The efficacy of parenteral gold after Ward, J.R.: Williams, H.1.: Egger, M.1.: Reading, J.C: Boyce, E.: auranofin failure in rheumatoid arthritis. Journal of Rheu­ Altz-Smith, M. et al.: Comparison of auranofin, gold sodium matology 10: 664 (1983). thiomalate, and placebo in the treatment of rheumatoid arth­ Williams, H.1.: A controlled clinical trial of auranofin, gold sod­ ritis: A controlled clinical trial. Arthritis and Rheumatism 26: ium thiomalate and placebo in rheumatoid arthritis. Arthritis 1303-1315 (1983c). and Rheumatism 25: 568 (1982). Ward. J.R.: Williams, H.1.: Egger, M.1.: Reading, J.C: Boyce, E.: Wolach, B.: De Board, J.E.: Baehner, R.L. and Boxer, L.A.: Mod­ Samuelson Jr, CO. et al.: Comparison of auranofin, gold sod­ ulation of leukocyte aggregation and degranulation by gold ium thiomalate and placebo in the treatment of active rheu­ compounds. Federation Proceedings 40: 753 (1981). matoid arthritis: Response by treatment duration: in Capell Wolach, B.: De Board, J.E.: Coates, T.D.: Baehner, R.L. and Boxer, et al. (Eds) International Symposium on Auranofin, pp. 115- L.A.: Correlation of in I'ilro and in I'ivo effects of gold com­ 134 (Excerpta Medica, Amsterdam 1983d). pounds on leukocyte function: Possible mechanisms of ac­ Weisman, M.H.: Albert, D.: Mueller, M.R. and Zvaifler, N.1.: tion. Journal of Laboratory and Clinical Medicine 100: 37-44 Gold therapy in patients with systemic lupus erythematosus. ( 1982). American Journal of Medicine 75 (Suppl. 6A): 157-164 (1983). Zurier. R.B.: Weissmann, G.: Hoffstein, S.: Kammerman, S. and Weisman, M.H. and Hannifin, D.M.: Management of rheuma­ Tai. H.H.: Mechanism of lysosomal enzyme release from hu­ toid arthritis with oral gold. Arthritis and Rheumatism 22: man leucocytes II. Effects of cAMP and cGMP autonomic 922-925 (1979). agonists and agents which affect microtubule function. Jour­ Weisman, M.H.: Hannifin, D.M.: Guerra, Jr, J.: Resnik, C and nal of Clinical Investigation 53: 297-309 (1974). Resnik, D.: Analysis of auranofin as a rheumatoid remitting agent. Journal of Rheumatology 9 (Suppl. 8): 132-136 (1982). Author's address: Michael O. Chl1(fman, ADIS Drug Information Weisman, M.H.: Hardison, W.G.M. and Walz, D.T.: Studies of Services. P.O. Box 34-030, Birkenhead, Auckland 10 (New the intestinal metabolism of oral gold. Journal of Rheuma- Zealand).

An ADIS Press Drug Information Journal

REACTIONS ADIS Press Issued twice a month, Reactions delivers succinct ADIS Press is an established privately owned reports from the current international literature on organisation of professional people skilled in the adverse drug reactions, interactions, overdose, techniques of retrieval, analysis, evaluation and poisoning, abuse and drug dependence. dissemination of information on medicine and Material is retrieved from over 1500 journals to give therapeutics, not affiliated with any professional, optimum speed, accuracy and coverage. governmental or trade association or group. The Most adverse drug reactions are predictable but too strength of the organisation centres around its full often the answers are inaccessible. Reactions, in just time inhouse professional editors and drug literature 15-20 minutes reading time per issue, will help you analysts. keep up with events in the world literature. ADIS Press medical publications and drug 22 issues a year, quarterly index and annual cumulation, information services are marketed in over 80 delivered by airmail. countries in 8 languages.