Search

Cocaine and amphetamine-regulated transcript (CART) mRNA and immunoreactivity are expressed abundantly in the hypothalamus. Central administration of various fragments of this neuropeptide decreases food intake in rodents. To find out whether CART might play a role in the physiological regulation of energy balance, we used in situ hybridization to investigate whether CART mRNA abundance changed in two chronic obese/fat versus lean states and after acute dietary restriction. In the first study, mice were treated with goldthioglucose to destroy glucose-responsive neurones in the ventromedial hypothalamus. This produced hyperphagia and obesity: 7 weeks after treatment, those receiving goldthioglucose weighed 70% more than the controls. CART mRNA abundance in the arcuate nucleus of goldthioglucose-treated mice was decreased by 71% compared to levels in the control mice, but CART expression was unaffected in the dorsolateral hypothalamus. In the second study, male Siberian hamsters were exposed to short days to induce a physiological winter response in which body weight decreases as fat reserves are catabolized, and food intake correspondingly declines. After 8 weeks in short days, body weight had declined by 18% relative to controls maintained in long days in a summer fat state. CART mRNA levels did not differ significantly between the two groups in any hypothalamic areas. In the third study, male Siberian hamsters, either in long days or after 12 weeks exposure to short days to induce weight loss, were subject to a 48-h period of fasting. Although photoperiod per se did not affect CART expression, fasting produced a significant decrease in CART mRNA in the arcuate nucleus of hamsters in both the long- and short-day state. We conclude that CART-producing cells are involved in energy homeostasis: the marked decrease in CART expression in the arcuate nucleus in goldthioglucose-lesioned mice may contribute to the development of obesity, and the decrease following acute dietary restriction in hamsters may reflect a compensatory mechanism to reduce caloric expenditure, but our results do not indicate that CART is involved in long-term seasonal regulation of body weight.

Apoprotein (apo) C-III plays an important role in the development of hypertriglyceridemia by inhibiting triglyceride (TG) removal. However, the effect of apo C-III on TG production remains unclear. We measured TG secretion rate (TGSR) in apo C-III gene-disrupted (apo C-III-null) mice to investigate the influence of this protein on TG turnover. TGSR measured by the Triton WR-1339 method was increased twofold in these mice compared with wild-type (WT) mice. Obesity was induced by the injection of gold-thioglucose (GTG), which made the WT mice hypertriglyceridemic due to a threefold increase of TGSR. However, GTG-induced obesity failed to increase TG in apo C-III-null mice, although TGSR was increased 10-fold, suggesting substantial stimulation of TG removal. Apo E-null mice were severely hypercholesterolemic but were not hypertriglyceridemic, and TGSR was rather decreased. GTG-induced obesity made these mice hypertriglyceridemic because of TG overproduction to an extent similar to that seen in WT mice. These results suggest that apo C-III deficiency potently enhances TG turnover, especially when TG production is stimulated, and that apo E deficiency is not always rate limiting for TG production.

Auranofin (triethylphosphine gold) was administered to 21 patients with juvenile rheumatoid arthritis during an open-ended, open-label, noncontrolled trial designed to establish safety and preliminary efficacy. Initial dosage was 0.1 mg/kg/day; incremental increases to 0.2 mg/kg/day were allowed. Aspirin (80 mg/kg/day), tolmetin (20 to 40 mg/kg/day), and naproxen (400 to 600 mg/m2/day) were allowed as rapidly acting anti-inflammatory agents. All patients attained measurable plasma concentrations of gold during the study. Clinically significant improvement (greater than 25%) occurred in more than half the patients with regard to the number and severity of joints with swelling, pain on motion, and tenderness. The number of joints with active arthritis decreased by at least 25% in nine of the 19 patients. Group mean changes between the initial and final visit indicated improvement in all articular disease indices measured. Eleven of 16 patients with an elevated erythrocyte sedimentation rate showed decreases of at least 25%. The group given the higher dosage had a greater proportion of responders with decreases in erythrocyte sedimentation rate. Four of six patients whose sera contained rheumatoid factor showed decreases in its titer. Discontinuation of auranofin was necessary in two patients because of headaches and because of hematuria and anemia associated with a severe flare of polyarticular disease, respectively. The results from this trial are sufficiently encouraging to merit a double-blind trial of auranofin in children with juvenile rheumatoid arthritis.

A comparison of placebo, auranofin, and parenteral gold sodium thiomalate therapy in 209 patients with active rheumatoid arthritis was performed in a 21-week prospective, controlled, double-blind multicenter trial. When the 161 patients who completed at least 20 weeks of treatment were analyzed for different degrees of response, no remissions were identified. When 50 percent or greater improvement of pain/tenderness scores were compared for end of trial versus entry values, 9 percent of placebo-treated patients, 34 percent of auranofin-treated patients, and 48 percent of gold sodium thiomalate-treated patients showed important improvement that was statistically significant for both gold treatments. When 50 percent improvement for joint swelling was analyzed, 12 percent of the placebo-treated group, 28 percent in the auranofin-treated group, and 37 percent in the gold sodium thiomalate-treated group showed this degree of improvement. Auranofin almost achieved statistical significance for improvement in joint swelling when compared with placebo (p = 0.07), but gold sodium thiomalate was much better than placebo (p = 0.009). There was no statistically significant difference between the two gold treatments. Thus it appears that a subset of patients had an important response to gold therapy that would not be evident by the usual analyses of mean or median changes. Analysis for predictors of response did not discriminate between responders and nonresponders. Because the trial was limited to 21 weeks of therapy, no prediction of the longer-term-effects, especially for auranofin, should be inferred.

The coordinated gold compound, 2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranosato-S-triethylphosphine-gold (auranofin) was found to be effective in increasing the life span of C57BL x DBA/2 F1 mice inoculated with the lymphocytic leukemia P388. A number of dose schedules were used, the lowest dose being 6 mg/kg every fourth day and the highest dose being 6.0 mg/kg twice daily for 9 days; the lowest and highest doses produced treated versus control ratios of 140 and 220%, respectively. All treatment groups achieved the minimum treated versus control ratio of 125%. Animal weights remained stable at twice-daily and high-dose-daily regimens. Increased life span and weight changes were both found to correlate with drug concentration and/or dose frequency.

X-rays from patients in comparative studies of auranofin and parenteral gold were obtained before and during treatment, and analysed using a modification of the method of Larsen. One hundred and nineteen auranofin-treated and 113 parenteral gold-treated patients contributed data, which were analysed for changes from 0-6 months, 0-12 months and from 0-6 and 12 months. Progression of erosive processes and of joint grade occurred with both treatments, but the proportion of patients with progression in the first six months was greater with auranofin treatment. However, there was evidence that both treatments produced slowing of the erosive process during the second six months of treatment.

In these experiments the effects of pharmacological concentrations of auranofin, a new absorbable gold compound, were assessed on the release of histamine and peptide leukotriene C4 (LTC4) from human basophils and lung mast cells. Auranofin, at pharmacological concentrations, inhibited in vitro histamine and LTC4 release from human basophils induced by anti-IgE. Inhibition began at about 3 X 10(-7) M and was maximum at 10(-5) M. We also evaluated the effect of auranofin on the release of histamine and LTC4 induced by anti-IgE from mast cells purified from human lung. Auranofin (3 X 10(-7) to 10(-5) M) dose-dependently inhibited the release of histamine and LTC4 from human lung mast cells. Thus pharmacological concentrations of auranofin cause dose-related inhibition of histamine release and de novo synthesis of LTC4 by human basophils and lung mast cells.

One hundred and twelve patients with classical or definite rheumatoid arthritis (RA) were randomly assigned to receive either sodium aurothiomalate (GSTM) or auranofin (AF). Monthly clinical assessments (morning stiffness, grip strength, articular index, pain, quality of life) and concurrent hematological, biochemical, and urine studies were performed to monitor the efficacy/toxicity (E/T) ratio. Ninety-two patients have completed 3 months; 65, 6 months; 47, 9 months; and 30, 12 months. The groups were numerically balanced at each time period. Analysis of the 0-6 month period suggests that both drugs were equally and significantly beneficial after 3 months and that this was maintained at 6 months. Toxicity was as frequent in both groups but more serious in the GSTM group. The main side effects were gastrointestinal (diarrhea) in the AF group and mucocutaneous in the GSTM group. Half of the withdrawals (14 in each group) were because of side effects in the GSTM group and for inadequate therapeutic efficacy in the AF group. This study suggests that after 6 months of treatment the E/T ratio of AF is greater than or equal to that of GSTM. These conclusions will need to be confirmed during the ongoing longer observation period. A significant clinical difference between the 2 drugs is that in a given patient treated with GSTM, the onset of toxicity coincides with a good therapeutic effect. This relationship does not appear to exist during AF treatment.

We compared auranofin (AF) in a single blind multi-centre study with gold sodium thiomalate and D-penicillamine in the treatment of rheumatoid arthritis. Adult patients with disease duration 6-60 months without previous treatment with gold salts with persistent active disease, were included. Thirty-nine patients, 13 in each treatment group, have so far been entered. Cumulative toxicity data and some results of efficacy assessments in those completing 9 months of treatment are presented. AF is very well tolerated, judgment concerning efficacy must await the end of the trial.

In view of encouraging results from various reliable multicenter studies, an interesting new oral agent, auranofin (triethylphosphine gold), is believed to be a major advance towards more effective treatment of rheumatoid arthritis with mild adverse reactions. The present study evaluates the long-term efficacy of auranofin in 46 patients with active rheumatoid arthritis and attempts to delineate further the results of drug monitoring concerning adverse reactions. Six patients withdrew due to untoward and partially serious events, e.g. thrombocytopenia, colitis or pancreatic disease. In view of the high frequency of side effects which required immediate withdrawal of auranofin in 13%, with a total of 37% of patients experiencing adverse reactions, it should be kept in mind that oral gold therapy may be a two-edged sword and requires further critical drug monitoring.

Two hundred eight patients were studied in a prospective, controlled, double-blind multicenter trial comparing auranofin (AUR), gold sodium thiomalate (GST), and placebo. One hundred sixty-one patients completed at least 20 weeks of therapy. Response to a variety of measures of efficacy was generally modest for both gold treatment groups although improvement was continuing in both groups at the end of the study. There was statistically significant improvement with both gold preparations compared to placebo for the number of tender joints, the joint tenderness score, and physician assessment of disease severity. GST was also significantly better than placebo for the joint swelling score. GST demonstrated more improvement in patients with anemia and thrombocytosis compared to the other treatment groups and both gold preparations were superior to placebo in improvement of an elevated erythrocyte sedimentation rate. Twenty-seven percent of patients on GST were withdrawn from the study for adverse drug reaction with rash and stomatitis being the predominant cause. Only 6% of patients on AUR were withdrawn for untoward drug effect. The time of onset of the adverse reactions is discussed. The two gold preparations were similar in efficacy although AUR was better tolerated.

A 63-year-old woman with seropositive rheumatoid arthritis was successfully treated with auranofin for 12 months. Heavy proteinuria then developed and the drug was stopped. However, the proteinuria apparently became worse. This was later recognised to be a spurious effect due to the introduction of tolmetin. Renal biopsy showed a type I membranous glomerulonephropathy.

The availability of an oral gold preparation in the treatment of rheumatoid arthritis, with a claim to being effective yet safer than parenteral gold, will most certainly attract the attention of physicians and patients who previously would not have used chrysotherapy. Cardinal clinical features that may be especially helpful to the nonrheumatologist in the diagnosis of rheumatoid arthritis are outlined. The often unpredictable course of rheumatoid arthritis is stressed, emphasizing the need for an adequate trial of nonsteroidal anti-inflammatory drug therapy before instituting the use of a potentially more toxic remission-inducing drug such as gold. The absence of an immediate flare of synovitis, should the use of oral gold be sporadic, will aggravate the problem of patient noncompliance. Techniques to minimize this problem will be noted. Perseverence and careful record keeping by physicians not necessarily comfortable with the long-term management of chronic disease must be part of the therapeutic program.

Auranofin [S-triethylphosphine gold-2,3,4,6 tetra-O-acetyl-l-thio-beta-D-glucopyranoside) SK&F 39162) has been administered at 0.1-0.25 mg/kg/day as the sole remission-inducing drug to 46 children affected with juvenile chronic arthritis (JCA). There were 22 males and 24 females; 12 children were affected with pauciarticular onset JCA, 26 with polyarticular onset JCA and 8 with systemic onset JCA. Three sets of efficacy criteria were evaluated quarterly: eight clinical, (Ritchie Index, number of affected, swollen and limited joints, number of joint with increased temperature, morning stiffness, Steinbrocker functional class, physician's disease evaluation), three hematochemical and one therapeutical. In most patients a panel of immunological parameters was routinely performed inclusive of peripheral blood lymphocyte subsets, serum immunoglobulins and C3c-C4 complement components. Patients who showed a definite improvement of at least two out of the three orders of efficacy criteria were classified as responders to auranofin. Out of the 35 patients evaluable after at least six months of treatment there were 24 (68%) responders. Nonresponders had a basal higher level of serum IgA and a basal lower level of serum C4. Both responders and nonresponders presented a reduction of the T4/T8 ratio during auranofin treatment, while only in responders did the basal high levels of IgG and C3c show a definite decrease.

In order to understand some of the unique toxic/therapeutic properties of the orally administered gold containing compound auranofin, the intestinal metabolism of gold was studied in 4 normal subjects. A triple lumen intestinal perfusion apparatus was used to measure intestinal flux using a non-absorbable radiolabelled marker dilution technique. Over a short (50 cm) segment of proximal small bowel, substantial disappearance of gold was observed; the findings, however, were most consistent with a loose, reversible adsorption onto the enteric cell surface rather than true trans-mucosal absorption. There was no evidence for an entero-hepatic recirculation of gold in these subjects or in 4 additional patients with rheumatoid arthritis studied in a similar manner.

The prevalence of eosinophilia in 82 rheumatoid arthritis patients receiving gold sodium thiomalate (GSTM) and 30 patients receiving auranofin (AF) was determined in a retrospective study. Eosinophilia occurred in 21% taking GSTM and in 13% on AF. The simultaneous occurrence of toxicity and eosinophilia occurred in 14% receiving GSTM and in 10% receiving AF. In contrast, eosinophilia only occurred in 24% of those with suspected toxicity receiving GSTM and in 30% of those with suspected toxicity receiving AF. The value of eosinophilia as a marker of toxicity is discussed.

The mechanisms of action of gold salts are still poorly understood. While Auranofin (AF) has a direct anti-inflammatory action in animal models, Myochrysin (MC) has not. Both gold compounds inhibit various enzymes. Among these, lysosomal enzymes are of particular interest. Gold is known to accumulate in the lysosomes, and gold salts modulate certain macrophage functions in the immune system. The role of organic gold salt ligands containing, like D-penicillamine, a thiol group is still unclear. Positive data characterizing responders versus nonresponders are not yet available. As in other clinically heterogeneous diseases, medical action has mainly been based on clinical empiricism which, although resting on false premises, has helped to find a comparatively efficacious treatment. In fact, the proposals for further studies to shed light on the mode of action presented here may equally be ill conceived. However, these studies would at least expand our understanding of rheumatoid arthritis and thus be beneficial in the long run.

Auranofin (AF) differs significantly from gold sodium thiomalate (GST) in formulation, i.e., aurous gold is stabilized by dual sulfur and phosphorus ligands, has hydrophobic rather than hydrophilic characteristics, and lacks ionic charge. These attributes facilitate: oral absorption of AF, plasma membrane penetration, increase in intracellular lymphocyte gold concentration and perhaps thereby influence lymphocyte function. AF therapy was observed to affect primarily T rather than B lymphocyte function in 16 RA subjects receiving 6 mg of AF per day for an average of 45 weeks (range 20-74 weeks) compared with GST-treated RA subjects. Lymphocytes from AF-treated subjects manifested prompt and sharp declines in mitogen-induced lymphoproliferative response (LPR); suppressed response to skin testing with dinitrochlorobenzene (DNCB); and blebbing of lymphocyte membranes as shown by scanning electron microscopy. Suppression of LPR with AF was approximately 60% after the first week and 80% after 20 weeks of therapy, contrasting with 0% and 30% for the respective intervals in GST-treated subjects. DNCB skin testing of AF patients, indicated 11 of 14, failed to respond, whereas all GST patients responded. Local or systemic fungal, bacterial and/or opportunistic infections were not encountered. The effect of AF on B cell effector function, e.g., suppression of immunoglobulins and rheumatoid factor titer, was less marked when contrasted with GST therapy in RA subjects, as previously reported.

The effect of sodium aurothiomalate and auranofin on the generation of superoxide anions (O2-) by polymorphonuclear leukocytes (PMNLs) and adherent mononuclear phagocytic cells (AMNCs) has been investigated. Sodium aurothiomalate at final concentrations of 1, 10, and 100 micrograms Au/ml and auranofin ranging from 0.1 to 2.0 micrograms Au/ml were used in the reactions involving all cell types. Results have been compared between cells drawn from normal controls and patients with active rheumatoid disease. The effect of gold compounds on both cell types was assessed following activation by phorbol myristate acetate (1 X 10(-8) M) and N-formyl-methionyl-leucyl-phenylalanine (1 X 10(-4) M) using a cytochrome c reduction method. Sodium aurothiomalate at the maximum concentration modestly inhibited O2- generation by PMNLs but not AMNCs. Auranofin inhibits O2- generation by both cell types. Inhibition of cells from patients with rheumatoid arthritis was greater than that seen with cells from normal controls.

Six rheumatoid arthritis (RA) patients were given 2 6 mg doses of auranofin (AF) containing Au195, 6 months apart. The radioactivity in the whole body and in plasma, urine, and stool samples was measured for 6 months after each dose. Absorption was rapid with peak plasma concentrations occurring 1.2-2 h post administration. 195Au plasma half-lives (t1/2) ranged from 11.0-31.3 days, with 195Au detectable in plasma for about 80 days. Total body t1/2 averaged 69.2+/-29.7 days. Urinary excretion accounted for 15% of the dose. Cumulative stool excretion was 89%, although 72% was excreted in 10 days. Continued stool excretion over 6 months suggested a "central-enteric" component to the excretory route.

The anti-inflammatory effects of auranofin were studied and compared with those of indomethacin, gold sodium thiomalate (GST) and D-penicillamine. Auranofin was active as indomethacin in inhibiting carrageenan induced paw edema in rats, but was less potent than indomethacin in inhibiting UV-induced erythema in guinea pigs. Auranofin inhibited Arthus type paw edema and reverse PCA reaction in rats, on which indomethacin was ineffective. The inhibitory activity of auranofin on adjuvant arthritis was weaker than that of indomethacin. In in vitro experiments, auranofin did not show any suppression of cyclooxygenase activity, but was capable of suppression of lysosomal enzyme release and chemotaxis of neutrophils and macrophages. In addition to these anti-inflammatory activities, auranofin had almost equal anti-analgesic and anti-pyretic activity to that of indomethacin. The above results indicated that the anti-inflammatory profiles of auranofin and indomethacin differ, so we can expect new therapeutic activities of auranofin. GST had similar anti-inflammatory and anti-analgesic profiles to those of auranofin; however, the activities were less potent than auranofin and devoid of anti-pyretic activity. D-penicillamine did not show any anti-inflammatory, anti-analgesic or anti-pyretic activity.

Oral gold (auranofin) has been used in 31 patients, 20 with active rheumatoid arthritis and 11 with active psoriatic arthritis. In rheumatoid arthritis the oral gold treatment was compared to parenteral gold treatment in a patient blind trial for two years. The psoriatic arthritis cases were incorporated in an open trial. Auranofin 6 mg once daily reduced significantly the activity in rheumatoid arthritis and in psoriatic arthritis. The beneficial effect obtained with auranofin at a dose of 6 mg/day during the first year of treatment could not be maintained by 3 mg/day in the second year. Auranofin compared to parenteral gold had a distinct advantage of better systemic tolerability, although parenteral gold was found to be more potent. There was no greater risk for toxic skin reaction to oral gold in psoriatic arthritis than in rheumatoid arthritis. The overall conclusion of this longterm study is that oral gold (auranofin) 6 mg once daily, although slightly less effective than parenteral gold, can be considered to be the first choice of gold treatment for rheumatoid arthritis and psoriatic arthritis, because the compliance, which is a reflection of a combination of tolerance and efficacy, for oral gold therapy was, in our hands, undoubtedly superior to parenteral gold.

The effects of gold on immune responses are reviewed. Gold salts used therapeutically can be followed by a decline in serum immunoglobulin levels, and rheumatoid factor titers in rheumatoid arthritis; in pemphigus there is similarly a drop in anti-epithelial antibody titers. Gold inhibits stimulation of immunoglobulin-secreting cells. Gold inhibits the activation of the classical and alternate complement pathways. Gold compounds inhibit numerous cell-mediated immune responses to various mitogens and antigens. Inhibition may be due to the effect of gold on macrophages acting as helper cell in these reactions. Auranofin is a new oral compound which seems to be particularly potent in its immuno-regulatory actions; it differs from other gold compounds in its pharmacokinetics, and in the nature of its ligand. Gold has also been reported to enhance certain immune reactions. The extent of the immuno-regulatory effects of gold in vivo is unknown, and the relation of these effects to its therapeutic actions remains to be clarified.

Forty patients with rheumatoid arthritis were randomly allocated to treatment with auranofin 3 mg b.d. or hydroxychloroquine 200 mg b.d. Twenty patients received each drug. Efficacy was analysed by comparing patients with available data at weeks 12, 24, 36 and 48 with baseline within each treatment group, and between treatment groups at each of these same time points. There were statistically significant improvements in all measured parameters of clinical efficacy among hydroxychloroquine treated patients, and in all efficacy parameters except one (time to onset of fatigue) in the auranofin treatment group. There were no significant differences between the treatment groups for any parameter of clinical efficacy. Of the laboratory parameters measured, only auranofin treatment produced statistically significant decreases in the concentration of IgA, IgG and IgM, with significant differences between treatments being detected in the case of IgA and IgG. Eight auranofin-treated and three hydroxychloroquine-treated patients were withdrawn because of adverse reactions before completing 48 weeks treatment. The commonest reason for stopping auranofin treatment was diarrhoea (5 cases). Three hydroxychloroquine-treated and two auranofin-treated patients were withdrawn from the study because of inefficacy of the trial drug. Auranofin had a more 'potent' biochemical profile than hydroxychloroquine, although more patients tolerated one year of treatment with the latter drug.

Despite a progressively more favorable prognosis in systemic lupus erythematosus (SLE) a need remains for therapeutic agents with greater benefit and less toxicity than corticosteroids and immunosuppressive drugs. Therefore, we treated 16 patients with SLE but without renal diseases with auranofin, a drug with proved efficacy and safety in rheumatoid arthritis. A modest diminution in overall disease activity, as judged by the investigators, and a reduction in maintenance corticosteroid dosage was achieved. However, neither laboratory assessments nor more objective clinical measurements of SLE disease activity disclosed any improvement over baseline. One case each of proteinuria and thrombocytopenia was observed, most likely related to underlying disease and not the drug, suggesting that auranofin may be safe in patients with SLE. A controlled trial, utilizing a broader spectrum of patients with SLE, may be warranted.

Auranofin is the first orally active gold compound for the treatment of rheumatoid arthritis. Like other chrysotherapeutic agents, its exact mechanism of action is unknown, but it probably acts via immunological mechanisms and alteration of lysosomal enzyme activity. Although long term clinical experience with auranofin is limited, its efficacy appears to approach that of sodium aurothiomalate. Further comparative studies with aurothioglucose, 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 effect on the occurrence or progression of erosive lesions. Auranofin is relatively well tolerated in most patients, but diarrhoea, skin rash, and pruritus are sometimes troublesome, and thrombocytopenia and proteinuria are potentially 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 effect seen with auranofin. The frequency of side effects has been similar with auranofin and sodium aurothiomalate, but 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 be necessary. Auranofin is clearly a useful addition to the limited list of agents with disease-modifying potential presently available for the treatment of rheumatoid arthritis. It will doubtless generate much interest as its final place in therapy becomes better defined through additional well-designed studies and wider clinical experience.

Human polymorphonuclear neutrophils (PMN) were treated with the antiinflammatory agents dexamethasone or Auranofin. PMN treated with dexamethasone in a dose range of 0.25-1 microM or Auranofin, 5-15 mM, were stimulated with 10(-7)M N-formyl-methionyl-leucyl-phenylalanine (FMLP). These agents were shown to inhibit the functional responses of degranulation and superoxide production in a dose-dependent manner. Similarly, the change in electrophoretic mobility, reflecting cell surface charge, was blocked. While both agents inhibited change in the fluorescence of the calcium chelate probe chlorotetracycline (CTC), the pattern of inhibition was significantly different. Dexamethasone appeared to inhibit the CTC response during its latter phases, while Auranofin inhibited all aspects of the CTC response. Auranofin was additionally shown to significantly decrease specific binding of FMLP, as well as the number of FMLP receptors. The two agents thus appear to act by different mechanisms. Dexamethasone is shown to have an effect on membrane-bound calcium release as measured by CTC, while Auranofin interferes with receptor binding.

Auranofin orally administered to rats resulted in delayed and protracted peak blood and serum gold levels occurring 24 to 48 h post administration. During this period, the gold concentration in blood was higher than in serum indicating that a major portion of gold was associated with the cellular components. During 1st order elimination (greater than 48 h), the blood/serum gold ratio decreased which suggested dissociation of cellular gold. Biliary cannulation experiments demonstrated that the protracted gold levels (24 to 48 h) could not be due to hepatic recirculation. In contrast to auranofin, gold sodium thiomalate produced blood gold levels which peaked within 3 h, rapidly declined and were consistently lower than serum gold levels.

Pharmacologic management of juvenile rheumatoid arthritis is only one of several modalities necessary for effective control. The stepping stones to proper management include a planned long-range program, physical therapy with swimming, good health habits, and consultation with other health professionals who are part of the management team. Pharmacologic therapy includes nonsteroidal anti-inflammatory drugs initially, occasionally corticosteroids, and slow-acting antirheumatic drugs, including injectable gold when therapeutic response is inadequate. Early experiences with oral gold are reported here. Auranofin (triethylphosphine gold) was administered to 21 patients with juvenile rheumatoid arthritis during a segment I, open ended, open-label, noncontrolled trial designed to establish safety and preliminary efficacy. Initial dosage was 0.1 mg/kg per day; incremental increases to 0.2 mg/kg per day were allowed (with usual increase to 0.15 mg/kg per day). Aspirin (80 mg/kg per day) or tolmetin (20 to 40 mg/kg per day), or naproxen (400 to 600 mg/m2 per day) were allowed as rapidly acting antiinflammatory agents. Stable measurable plasma concentrations of gold were attained in all patients during the study. More than half the patients sustained clinically significant improvement (greater than 25 percent) with regard to the number and severity of joints with swelling, pain on motion, and tenderness. In nine of the 19 patients, the total number of joints with active arthritis decreased by at least 25 percent. All articular disease indices measured indicated improvement of group mean changes between the initial and final visit. Eleven of 16 patients with an elevated erythrocyte sedimentation rate showed decreases of at least 25 percent. The group given higher dosages had a greater proportion of responders in regard to decreases in erythrocyte sedimentation rate (nine of 11 patients). Four of six patients whose serums contained rheumatoid factor showed decreases in the titers. Discontinuation of auranofin was necessary in two patients: one because of headache and one because of hematuria and anemia associated with a severe flare-up of polyarticular disease. The results from this trial reveal sufficient patient improvement to plan a double-blind trial of auranofin in children with juvenile rheumatoid arthritis.

Auranofin (AF; ' Ridaura '), an oral chrysotherapeutic agent, parenteral gold sodium thiomalate (GST) and gold thioglucose (GTG) were evaluated in order to compare their preclinical profiles. AF was found to be more effective than GST and GTG in suppressing inflammation and stimulating cell-mediated immunity. In contrast to GST, AF inhibited cellular release of lysosomal enzymes, antibody-dependent cellular cytotoxicity, production of antibodies in adjuvant arthritic rats, and antibodies involved in cytotoxicity reactions. In pharmacokinetic studies, plasma gold in rats following AF administration, exhibited greater cell association than after GST administration. In conclusion, the pharmacological profile of AF is markedly different from those of GST and GTG and this suggests potential for improvements in chrysotherapy.

Roentgenograms of hands and wrists from rheumatoid arthritis patients treated with auranofin for 12 and 24 months were scored for severity of erosive disease. Scores were analyzed by a method in which a calculated mean annual rate of erosion prior to treatment was compared with the annualized rate during therapy. The original films from a previous Myochrysine versus placebo study were reanalyzed in order to compare the results of different scoring methods and to provide an auranofin versus placebo comparison. Two readers found the rate of erosion during oral gold therapy to be less than that predicted by the analytical model. Interobserver differences in scoring were demonstrated. A breakdown of patient scores by duration of disease showed the greatest difference between scores observed during treatment with those predicted by the model in patients with early disease.

The effects of an orally active gold complex, auranofin, were investigated on the isolated guinea pig trachea contracted pharmacologically and antigenically. Pretreatment of the tracheal tissues for 15 minutes with auranofin (10(-5) and 10(-4) mol/L) produced a significant rightward shift of a histamine dose-response curve (p less than 0.001), whereas a 30-minute pretreatment with auranofin (10(-4) mol/L) inhibited LTD4-induced (but not LTC4-induced) contraction of the tracheal spirals. In tracheas from animals actively sensitized to ovalbumin, auranofin (10(-4) mol/L) significantly inhibited contractions elicited by 0.01 micrograms/ml of this antigen. Auranofin does not appear to behave like a nonspecific suppressant of tracheal muscle contraction since it failed to antagonize a potassium chloride-induced (6 X 10(-2) mol/L) contraction. Therefore, auranofin appears to alter the in vitro response of the guinea pig trachea not only to histamine but also, more importantly, to LTD4 and specific antigen. These results characterize and extend further the pharmacology of auranofin in airway tissue.

Auranofin and cisplatinum have antiarthritic, and antineoplastic activities respectively. Because of the chemical and biological similarities of the two compounds and the extensive studies on molecular pharmacology of cisplatinum, the information about the molecular and pharmacologic effects of these agents is presented and compared. Gold and platinum complexes both can exist in several oxidation states and form coordinate complexes of varying geometry and complexity. Gold complexes interact with bases and nucleosides but relatively little is known about their interaction with polynucleotides. Extrapolating from an understanding of the interactions of platinum complexes with polynucleotides, a number of proposals for additional research on gold complexes are presented. Substantially more information is available concerning the interactions of gold complexes and various proteins. The effects of gold complexes on intracellular macromolecules and their synthesis are poorly understood and should be studied using systems employed to study platinum analogues. It is suggested that 2 dimensional gel electrophoresis of various cellular proteins be employed to determine to which intracellular protein gold complexes bind.

The effect of auranofin, an oral chrysotherapeutic agent, on histamine release from human basophils was studied. Auranofin inhibited IgE-mediated, anti-IgE-induced histamine release in a dose-dependent fashion with a concentration of drug required to produce 50% inhibition of 1.3 micrograms/ml. This compound also inhibited calcium ionophore A23187 and 12-0-tetradecanoyl-phorbol-13-acetate-induced histamine release with a concentration of drug required to produce 50% inhibition of 1.7 micrograms/ml and 0.9 micrograms/ml, respectively. Auranofin was less active for formyl-L-methionyl-L-leucyl-L-phenylalanine-induced release of histamine with 32 +/- 10% (mean +/- SEM) inhibition at 2 micrograms/ml. Auranofin effects were reversible when leukocytes preincubated with auranofin was washed with buffer. In contrast, gold sodium thiomalate enhanced IgE-mediated histamine release, suggesting that these two compounds exert their actions at different levels. These results suggest that auranofin may be beneficial to patients with allergic diseases such as bronchial asthma.

The pharmacokinetics of oral gold (auranofin) in some respects resemble, and in other respects differ from, those of existing parenteral gold compounds such as gold sodium thiomalate (GST). This may in part relate to physicochemical differences as GST is a water-soluble polymeric compound in vitro whereas auranofin is lipid-soluble and characteristically monomeric. Furthermore, intramuscularly administered gold is greater than 95% bioavailable, whereas only 20 to 30% of an orally administered dose of auranofin is absorbed. Following a standard 50mg intramuscular injection of GST, serum gold concentrations rise sharply, peaking between 4 and 8 mg/L in approximately 2 hours and declining to an average of 3 mg/L by 7 days. With repeated injections of GST stable serum concentrations of gold (3 to 5 mg/L) are eventually achieved (usually within 5 to 8 weeks) although absolute concentrations may vary widely between patients. On the other hand, long term treatment with auranofin is associated with lower and more stable serum concentrations of gold (0.5 to 0.7 mg/L), on the standard dosing regimen of 6 mg daily. Both compounds are retained within the body for prolonged periods. However, the amount of gold retained with auranofin is significantly less compared with GST (less than 5% of a tracer dose of auranofin--about 20% of the absorbed dose--is retained by 100 days whereas the retention for a single labelled dose of GST over a similar interval is greater than 50%). Excretory patterns of GST and auranofin also differ. Most of an absorbed dose of GST (greater than 70%) is excreted by the kidneys whereas only 50% of an absorbed (15% of an administered) dose of auranofin is excreted in the urine. Both compounds are avidly bound by plasma proteins and auranofin shows a particularly strong association with circulating cellular elements. In human subjects, parenterally administered gold is widely distributed among bodily tissues, showing a predilection for tissues of the reticuloendothelial system as well as the kidney and adrenal cortex. Comparable studies in humans are not available for auranofin but animal studies have shown comparatively less affinity for the liver, kidney and spleen. Valuable insight has been gained in analysing the comparative pharmacokinetics of oral and injectable gold compounds. Unfortunately, attempts to correlate pharmacokinetic findings with clinical response or pharmacodynamic changes, as a whole, remain largely unsuccessful with these agents.

Problems in trials of disease-remittive agents include the slow action and late side effects of these compounds, the lack of immediate benefit to the patient, their characteristic and sometimes dangerous side effects, variability of response, natural fluctuation of the disease, and uncertain definition of drug types. To overcome these problems, trials must be of long duration with large numbers of patients whose characteristics are clearly defined. The 2/3 blind technique overcomes the problem of side effects. Measurements must include aspects of the disease state as well as its articular manifestations. Criteria for the identification of disease-remittive agents include effects in animal models of inflammation, time course, disease-dependence, effects on joint disease and extraarticular manifestations, changes in erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), and immunoglobulins, radiological progression, outcome, and perhaps side effects. The time course of the action of auranofin (AF), similar to that of Myochrysine, with its effects on ESR and RF, support the view that AF is a disease-remittive agent.

A prospective controlled, double-blind multicenter trial compared placebo, auranofin (an orally administered gold complex), and parenteral gold sodium thiomalate (GST) in patients with active rheumatoid arthritis (RA). Of 193 patients who received any treatment, the only important improvement identified for either auranofin or GST was for pain/tenderness scores. When 161 patients who completed 20 weeks of treatment were examined, both auranofin and GST treatments were superior to placebo as measured by improvement in number of painful and/or tender joints, joint pain/tenderness scores, physician's assessment of disease activity, and decrease in erythrocyte sedimentation rate when elevated at entry. GST was superior to placebo in improvement of joint swelling scores, anemia, thrombocytosis, and rheumatoid factor. No drug-related remissions were observed. The only statistically significant advantages of GST over auranofin for efficacy were an increase in hemoglobin concentration and decrease of thrombocytosis with GST. Withdrawals for adverse effects were 5 times more frequent with GST treatment. Thrombocytopenia, proteinuria, elevated liver enzymes, "nitritoid" reactions, and "gold pneumonitis" were observed only in the GST treatment group. These results confirm that both parenteral and oral gold may be effective for the treatment of RA, that GST tends to show greater efficacy than auranofin, and that auranofin has fewer significant adverse effects than GST. However, long-term benefits, tolerability, and safety cannot be inferred from this study.

Auranofin, an orally effective gold compound, was administered to 2 groups of rheumatoid arthritis patients at 2 mg and 6 mg daily respectively in a controlled study. Both groups showed significant improvement in most efficacy measurements by 6 months. More improvement measurements were observed in the 6 mg group at 3 months than the 2 mg group. Dropout rate because of diarrhea was similar in the 2 groups. Other adverse reactions severe enough to force withdrawal of the test drug were infrequent.

Therapeutic serum concentrations of auranofin, expressed as elemental gold, range from 0.25 - 1.0 micrograms/ml. Monocyte antibody dependent cellular cytotoxicity (ADCC) could be reduced by up to 50% at a gold concentration of 0.125 micrograms/ml. Lymphocyte ADCC was much less dramatically affected although 2.5 micrograms/ml produced virtually complete inhibition. The most surprising finding is a marked stimulation of natural killer (NK) cell activity using a variety of targets. NK activity was markedly enhanced by concentrations of 0.125 to 0.5 micrograms/ml (range 2-500%). This is a biphasic dose dependent response. 1.0 micrograms/ml was depressive and 2.5 micrograms/ml completely abolished NK cell activity. Whether these selected in vitro responses play a role in modulating tissue damage in vivo is yet to be determined.

We investigated the therapeutic effect of two gold salts, gold sodium thiomalate (GST, i.m.) and auranofin (p.o.), D-penicillamine (p.o.) and benoxaprofen (p.o.) in rat collagen-induced arthritis using type II collagen from fetal bovine articular cartilage. GST, but not auranofin, reduced hind paw edema and bone pathology. However, auranofin reduced serum copper and zymosan-induced prostaglandin production from peritoneal macrophages. In contrast, GST increased both serum copper and macrophage prostaglandin production by zymosan. Benoxaprofen reduced both hind paw edema and pathology, whereas D-penicillamine was without effect. None of these treatments influenced the circulating level of antibody to type II collagen.

Drugs like penicillamine act slowly, benefit extraarticular features of the disease as well as the joints, reduce erythrocyte sedimentation rate and rheumatoid factor titer and may slow the progression of radiographic changes and alter the outcome of the disease. Their action is to some extent disease-dependent. The 1st choice of drugs of this type is now penicillamine. It compares favourably with other drugs of the same type including gold, azathioprine and levamisole. A number of compounds in the development stage offer potential advantages over currently available drugs of this class. A compound which was safe enough to be recommended for widespread use would take over the role of first-line treatment of rheumatoid arthritis.

The effects of auranofin on the function of neutrophil polymorphonuclear granulocytes (PMN) have been studied in vitro and in vivo. Preincubation of human PMN with auranofin (1-4 micrograms/ml) increased their adherence to nylon fibres and f-met-leu-phe-(fMLP) induced aggregation. PMN migration, phagocytosis, bactericidal capacity and phagocytosis-associated enzyme release were all significantly inhibited by auranofin in a dose-dependent way. Enzyme release stimulated by f-MLP, chemoluminescence and the release of superoxide anions all showed a biphasic response to preincubation with auranofin. They showed an increase at low concentrations and inhibition at high concentrations. In studies of 3H-fMLP binding auranofin did not affect receptor numbers but increased binding affinity. Auranofin at higher concentrations decreased phorbolmyristate acetate and fMLP induced changes in surface charge and membrane potential. In vivo, auranofin administered to rats, did not prevent either the neutropenia induced by zymosan-activated serum or the corresponding rise in plasma lactoferrin levels. PMNs from six rheumatoid arthritis patients treated with auranofin (6 mg/day) for 23 weeks showed changes in bactericidal activity, chemotaxis and chemiluminescence independent of the clinical response. Enzyme release, however, was reduced in PMNs from clinical responders and showed no change in non-responders.