Control of Oxidative Damage in Rheumatoid Arthritis By Gold(I)-Thiolate Drugs

The roles of anti-arthritic gold(I)-thiolate drugs such as disodium aurothiomalate (‘Myocrisin’) in the modulation or promotion of oxygen radical-mediated oxidative damage in vivo ate reviewed. In particular, the precise molecular mechanisms by which these novel second-line agents exert their therapeutic effects are discussed in terms of (i) the direct and indirect control of enzymes involved in the generation or scavenging of reactive oxygen speices (ROS) such as superoxide ion, hydrogen peroxide and hydroxyl radical, (ii) the protection of proteins and relevant enzyme systems against attack by ROS and (iii) their direct involvement in the production (at appropriate ‘target’ sites) or scavenging of ROS in vivo. In addition, the role of the orally-effective gold(I)-phosphine complex auranofin in the control of oxidative damage in rheumatoid arthritis is also discussed.     

Induction of mammalian stress proteins by a triethylphosphine gold compound used in the therapy of rheumatoid arthritis

In vitro exposure of cultured human, murine and rat cells to pharmacologic concentrations (10(-8) to 10(-6) M) of auranofin, 2,3,4,6,-tetra-O-acetyl-1-thio-beta-D-glucopyranosato-S- triethylphosphine gold(I) (Ridaura), a gold containing compound approved for the treatment of rheumatoid arthritis, results in the induction of several stress proteins. The enhanced synthesis of two polypeptides, p32 and p34, was particularly prominent. A similar response was observed in freshly collected human monocytes challenged with auranofin. In addition, oral administration of auranofin to rats induced enhanced synthesis of a 32-kDa protein in peritoneal exudate cells analyzed ex vivo at various times following drug treatment. These data suggest that increased synthesis of p32 and p34 might participate in mediating certain aspects of auranofin pharmacology.     

阿达木单抗注射液联合白芍总苷治疗甲氨蝶呤不耐受型类风湿关节炎的临床疗效

目的:探讨阿达木单抗注射液联合白芍总苷治疗甲氨蝶呤不耐受风湿关节炎患者的临床疗效。方法:收集我院治疗的86例甲氨蝶呤不耐受的类风湿关节炎患者,随机分为实验组和对照组,每组43例。对照组患者给予阿达木单抗注射液治疗,实验组患者在对照组基础上给予白芍总苷胶囊治疗。观察并比较两组患者的晨僵时间、血沉(ESR)、类风湿因子(FR)以及临床疗效进行检测并比较。结果:与治疗前相比,治疗后两组患者的晨僵时间、血沉(ESR)、类风湿因子(FR)水平均下降(P0.05);与对照组相比,实验组患者的晨僵时间、血沉(ESR)、类风湿因子(FR)水平较低(P0.05),临床治疗有效率较高(P0.05)。结论:阿达木单抗注射液联合白芍总苷能够降低甲氨蝶呤不耐受的类风湿关节炎患者的ESR、FR水平,改善患者的临床症状,临床疗效较好。     

Evidence that the antiproliferative effects of auranofin in Saccharomyces cerevisiae arise from inhibition of mitochondrial respiration

Auranofin is a gold based drug in clinical use since 1985 for the treatment of rheumatoid arthritis. Beyond its antinflammatory properties, auranofin exhibits other attractive biological and pharmacological actions such as a potent in vitro cytotoxicity and relevant antimicrobial and antiparasitic effects that make it amenable for new therapeutic indications. For instance, auranofin is currently tested as an anticancer agent in four independent clinical trials; yet, its mode of action is highly controversial. With the present study, we explore the effects of auranofin in Saccharomyces cerevisiae and its likely mechanism. Notably, auranofin is reported to induce remarkable yeast growth inhibition. Solid evidence is provided that growth inhibition is the consequence of a direct cytotoxic insult occurring at the mitochondrial level; a profound depression of cell respiration is indeed clearly documented as the main cause of cell death while induction of ROS plays only a secondary role. More in detail, the mitochondrial NADH kinase Pos5 is identified as a primary target for auranofin. The implications of these results are discussed in the frame of current mechanistic knowledge on the cellular effects of auranofin and of its role as a prospective anticancer drug.     

Control of Oxidative Damage in Rheumatoid Arthritis By Gold(I)-Thiolate Drugs

The roles of anti-arthritic gold(I)-thiolate drugs such as disodium aurothiomalate ('Myocrisin') in the modulation or promotion of oxygen radical-mediated oxidative damage in vivo ate reviewed. In particular, the precise molecular mechanisms by which these novel second-line agents exert their therapeutic effects are discussed in terms of (i) the direct and indirect control of enzymes involved in the generation or scavenging of reactive oxygen speices (ROS) such as superoxide ion, hydrogen peroxide and hydroxyl radical, (ii) the protection of proteins and relevant enzyme systems against attack by ROS and (iii) their direct involvement in the production (at appropriate 'target' sites) or scavenging of ROS in vivo. In addition, the role of the orally-effective gold(I)-phosphine complex auranofin in the control of oxidative damage in rheumatoid arthritis is also discussed.     

Comparison between penicillamine and sulphasalazine in rheumatoid arthritis: Leeds-Birmingham trial.

Sulphasalazine was first formulated by Svartz in the early 1940s, specifically for use as a remission inducing drug in rheumatoid arthritis. After the publication of an unfavourable trial, however, the drug was restricted to patients with ulcerative colitis. In the late 1970s sulphasalazine was re-examined in rheumatoid arthritis and favourable results reported in "open" trials. A double blind controlled trial was therefore conducted comparing enteric coated sulphasalazine and D-penicillamine in patients with active rheumatoid arthritis. A total of 63 patients were recruited in two centres; 31 were treated with sulphasalazine and 32 received penicillamine. After 16 weeks'' treatment both drugs had produced significant improvements in clinical score, pain score measured on a visual analogue scale, grip strength, Ritchie articular index, erythrocyte sedimentation rate, and serum C reactive protein concentration. Nausea was the major side effect in the sulphasalazine treated group. No potentially dangerous effects of sulphasalazine were encountered in contrast with those seen in the penicillamine group. The results suggest that sulphasalazine is an effective and safe drug capable of producing remissions in active rheumatoid arthritis. They also lend confidence to the use of preliminary "open" trials as a means of screening for remission inducing drugs in rheumatoid arthritis.     

Inhibition of production of macrophage-derived angiogenic activity by the anti-rheumatic agents gold sodium thiomalate and auranofin

We have investigated the effect of gold sodium thiomalate and auranofin, gold compounds employed in the treatment of rheumatoid arthritis, on production of macrophage-derived angiogenic activity. Elicited mouse peritoneal macrophages were cultured in the presence or absence of gold compounds or thiomalic acid, and the macrophages or their conditioned media were then assayed for their angiogenic activity in rat corneas. Control macrophage conditioned medium was potently angiogenic. In contrast, conditioned medium from gold or thiomalic acid treated macrophages was not. Addition of gold compounds or thiomalic acid to control macrophage conditioned medium did not inhibit its angiogenic activity. Drug treatments did not significantly affect macrophage lactate dehydrogenase release, lysozyme release, or protein synthesis. We conclude that gold sodium thiomalate and auranofin potently reduce the detectable angiogenic activity produced by macrophages.     

Inhibition of lysosomal cysteine proteases by chrysotherapeutic compounds: a possible mechanism for the antiarthritic activity of Au(I)

Although Au(I) complexes have been used to treat rheumatoid arthritis for over 75 years, their mechanism of action is still poorly understood. A family of enzymes responsible for joint destruction in rheumatoid arthritis, the cathepsins, has been discussed as a possible biological target of Au(I). In this study, inhibition of the cathepsins by known Au(I) drugs and related compounds was investigated. The compounds tested inhibited cathepsin activity with IC50 values as low as 600 nM. More typical IC50 values were in the 50-200 microM range. Although the gold complexes are not extremely potent cathepsin inhibitors, it is likely that this inhibition is biologically relevant given the high concentrations of Au(I) in the serum and joints of patients undergoing chrysotherapy. While it is likely that there are multiple targets of Au(I) in vivo, inhibition of the cathepsins would provide protection against the joint destruction that is a hallmark of rheumatoid arthritis and is one possible mechanism for Au(I) antiarthritic activity.     

Comparison of treatment outcome in patients with rheumatoid arthritis treated with TFX- Polfa or gold salts after a one year follow up]

Thirty five patients with rheumatoid arthritis were given TFX Polfa, initially everyday in the intramuscular injections in the dose of 10 mg TFX protein for 60 days, followed by 1 injection of 10 mg TFX protein a week for 10 months. Other 30 patients with rheumatoid arthritis treated with gold salts were used for comparison. Several clinical and laboratory tests were performed before the treatment and after 1 year. A one-year therapy significantly improved all clinical parameters in both groups. A significant increase in hemoglobin and erythrocyte count was noted in patients treated with TFX. A significant decrease in the markers of inflammation was seen. A percentage of both early and delayed E rosettes increased highly significantly. The obtained results suggest that TFX Polfa is efficient in these cases of the rheumatoid arthritis which cannot be treated with gold salts.     

Calorie restricted diet and urinary pentosidine in patients with rheumatoid arthritis

Low-energy diets and fasting have suppressive effects on rheumatoid arthritis. It was reported recently that urine levels of pentosidine (i.e., an advanced glycation end product formed by glycosylation) is associated with the activity of rheumatoid arthritis. We conducted a regimen of caloric restriction combined with fasting in patients with rheumatoid arthritis, and then evaluated urinary pentosidine levels. Ten patients with rheumatoid arthritis underwent a 54-day caloric restriction program. Urinary pentosidine levels were measured and the Lansbury Index were determined by examining the clinical features, blood biochemistry and the inflammation activity of rheumatoid arthritis on days 0, 25 and 54. On day 0, the mean urinary pentosidine level of patients with rheumatoid arthritis was significantly higher than that of the control subjects. On day 54, the mean body weight had reduced due to caloric restriction. The mean values of the erythrocyte sedimentation rate and the Lansbury Index of patients both significantly decreased during the study. In addition, although the urinary pentosidine levels showed no significant difference between day 0 and 25, it was significantly decreased at the end of the study (day 54). The study showed that under a low energy diet a reduction of disease activity in rheumatoid arthritis was accompanied with a reduction of the urinary pentosidine.     

Does the order of second-line treatment in rheumatoid arthritis matter?

In a prospective study 88 patients, with rheumatoid arthritis who had stopped taking gold, penicillamine, or levamisole were randomly allocated to one of the alternative drugs and followed up for a minimum of one year. Concurrent studies of the effects of gold, penicillamine, and levamisole prescribed in 123 patients as the first second-line drug were used for comparison. No difference in toxicity or efficacy between primary and secondary use of gold or penicillamine was identified. Variation in the toxicity of levamisole could in part be accounted for by changes in the dose regimen over the four years of study. The length of the treatment-free interval between drugs did not influence subsequent development of toxicity. These results suggest that an adverse reaction to one of the three second-line drugs studied should not prejudice the selection of another.     

Inhibition of cathepsin B by Au(I) complexes: a kinetic and computational study

Gold(I) compounds have been used in the treatment of rheumatoid arthritis for over 80 years, but the biological targets and the structure–activity relationships of these drugs are not well understood. Of particular interest is the molecular mechanism behind the antiarthritic activity of the orally available drug triethylphosphine(2,3,4,6-tetra-O-acetyl-β-1-d-thiopyranosato-S) gold(I) (auranofin, Ridaura). The cathepsin family of lysosomal, cysteine-dependent enzymes is an attractive biological target of Au(I) and is inhibited by auranofin and auranofin analogs with reasonable potency. Here we employ a combination of experimental and computational investigations into the effect of changes in the phosphine ligand of auranofin on its in vitro inhibition of cathepsin B. Sequential replacement of the ethyl substituents of triethylphosphine by phenyl groups leads to increasing potency in the resultant Au(I) complexes, due in large part to favorable interactions of the more sterically bulky Au(I)–PR₃ fragments with the enzyme active site.     

Remission-inducing drugs in rheumatoid arthritis.

The administration of certain drugs to patients with established rheumatoid arthritis frequently results in improvement that is slow to appear but persists for long periods, even after the drug is discontinued. The three main drugs with this effect, whose efficacy and toxicity are reviewed in this paper, are gold salts, D-penicillamine and chloroquine. The cytotoxic agents used to treat rheumatoid arthritis, which likely have nonspecific anti-inflammatory actions and have serious long-term side effects, are also briefly reviewed. A new drug, levamisole, is currently being tested in patients with rheumatoid arthritis. It is suggested that the time for considering the introduction of a remission-inducing drug in patients with progressive rheumatoid arthritis is after an adequate trial of therapy with salicylates or other nonsteroidal anti-inflammatory agents, or both, and before the oral administration of steroids. It is difficult, however, on the basis of rigorous clinical comparisons, to recommend which of the three main remission-inducing drugs should be tried first, although gold salts have been used the most. Patients who have improved with 6 months of chrysotherapy may continue treatment for at least 3 years, during which time the frequency of mucocutaneous and renal toxic effects will steadily decrease. Some aspects of the medical economics of therapy with remission-inducing drugs for rheumatoid arthritis are discussed.     

SALICYLAZOSULFAPYRIDINE (SALAZOPYRIN OR AZOPYRIN) IN RHEUMATOID ARTHRITIS AND EXPERIMENTAL POLYARTHRITIS

Thirty patients with rheumatoid arthritis were treated with Salazopyrin® for periods from two months to one year.Fourteen patients were symptomatically relieved in varying degrees. This group included seven patients not previously benefited by gold therapy and four who had had toxic reaction to gold. The sedimentation rates tended to remain elevated in spite of symptomatic improvement. Extension of disease to joints not formerly involved appeared in only one patient under treatment.Continuation of small dosage for long intervals seemed advantageous in the small number of patients treated in this study.Fourteen patients were not relieved symptomatically by Salazopyrin, but they did not become worse. This group included eight patients with severe, advanced disease, six of whom had not been benefited by chrysotherapy.In one patient there was a moderate reduction in erythrocyte count and in hemoglobin. One patient refused medication, claiming extreme nervousness.Salazopyrin is variably and comparatively poorly absorbed in man.In experimental polyarthritis of rats, administration of 0.5 per cent Salazopyrin in the diet produced a slight beneficial effect, while 1 per cent made the infection worse. Changes in body weight and in leukocyte content in the blood of rats and mice showed Salazopyrin to have minimal toxic effect in these rodents.     

Pyridoxine supplementation corrects vitamin B6 deficiency but does not improve inflammation in patients with rheumatoid arthritis

Patients with rheumatoid arthritis have subnormal vitamin B6 status, both quantitatively and functionally. Abnormal vitamin B6 status in rheumatoid arthritis has been associated with spontaneous tumor necrosis factor (TNF)-α production and markers of inflammation, including C-reactive protein and erythrocyte sedimentation rate. Impaired vitamin B6 status could be a result of inflammation, and these patients may have higher demand for vitamin B6. The aim of this study was to determine if daily supplementation with 50 mg of pyridoxine for 30 days can correct the static and/or the functional abnormalities of vitamin B6 status seen in patients with rheumatoid arthritis, and further investigate if pyridoxine supplementation has any effects on the pro-inflammatory cytokine TNF-α or IL-6 production of arthritis. This was a double-blinded, placebo-controlled study involving patients with rheumatoid arthritis with plasma pyridoxal 5'-phosphate below the 25th percentile of the Framingham Heart Cohort Study. Vitamin B6 status was assessed via plasma and erythrocyte pyridoxal 5'-phosphate concentrations, the erythrocyte aspartate aminotransferase activity coefficient (αEAST), net homocysteine increase in response to a methionine load test (ΔtHcy), and 24 h urinary xanthurenic acid (XA) excretion in response to a tryptophan load test. Urinary 4-pyridoxic acid (4-PA) was measured to examine the impact of pyridoxine treatment on vitamin B6 excretion in these patients. Pro-inflammatory cytokine (TNF-α and IL-6) production, C-reactive protein levels and the erythrocyte sedimentation rate before and after supplementation were also examined. Pyridoxine supplementation significantly improved plasma and erythrocyte pyridoxal 5'-phosphate concentrations, erythrocyte αEAST, urinary 4-PA, and XA excretion. These improvements were apparent regardless of baseline B6 levels. Pyridoxine supplementation also showed a trend (p < 0.09) towards a reduction in post-methionine load ΔtHcy. Supplementation did not affect pro-inflammatory cytokine production. Although pyridoxine supplementation did not suppress pro-inflammatory cytokine production in patients with rheumatoid arthritis, the suboptimal vitamin B6 status seen in rheumatoid arthritis can be corrected by 50 mg pyridoxine supplementation for 30 days. Data from the present study suggest that patients with rheumatoid arthritis may have higher requirements for vitamin B6 than those in a normal healthy population.     

He-Ne激光结合丹参对类风湿性关节炎大鼠血液流变学指标的影响

目的:研究He-Ne激光结合丹参对类风湿性关节炎大鼠的治疗效果,以便为临床提供治疗风湿病的参考依据。方法:通过对健康大鼠注射鸡Ⅱ型胶原诱导后,成功建立了大鼠类风湿性关节炎的模型,随机分组后给予治疗,分析大鼠体重、血液流变学指标的变化。结果:1.与空白对照组相比,不同处理组大鼠类风湿关节炎体重增长幅度不同(P<0.05),其中模型组最小,丹参结合激光治疗组最高。2.与空白对照组相比,不同处理组的全血还原粘度低切、全血粘度(低、中、高切)、红细胞聚集指数均降低(P<0.05),其中模型组大鼠最高;而激光结合丹参治疗组最低。但全血还原粘度中、高切和红细胞压积没有统计学差异(P>0.05)。结论:丹参结合激光对Ⅱ型胶原诱导类风湿性关节炎大鼠体重、血液流变学指标均有一定程度的改善。     

类风湿关节炎与痛风关节炎患者身心健康、炎症状态及免疫功能的比较

目的:比较类风湿关节炎与痛风关节炎患者身心健康、炎症及免疫状态的差异。方法:选择我院2016年5月至2018年8月收治的66例类风湿关节炎患者及63例痛风关节炎患者作为研究对象,并将之分为类风湿关节炎(Rheumatoid arthritis,RA)组及痛风关节炎(Gouty arthritis,GA)组。同时选取60例体检健康人群作为健康组。观察比较三组研究对象身心健康评分、炎症及免疫相关指标水平。结果:RA组及GA组身心健康评分显著低于健康组(P0.05),炎症及免疫相关指标水平显著高于健康组(P0.05)。RA组患者总体健康评分、社会功能评分、红细胞沉降率(ESR)、C反应蛋白(CRP)、免疫球蛋白G(Ig G)、免疫球蛋白A(Ig A)、免疫球蛋白M(Ig M)及补体3(C3)水平显著高于GA组(P0.05),白细胞(WBC)总数明显少于GA组(P0.05),两组患者生理功能、生理职能、身体疼痛、活力、情感职能、心理健康评分及补体4(C4)水平比较差异不显著(P0.05)。结论:相较于健康人群,类风湿关节炎患者及痛风关节炎患者身心健康状况差,易出现炎症、免疫功能紊乱现象,且类风湿关节炎患者炎症程度较深,免疫功能影响更大。     

Ploidity and cell cycle progression during treatment with gold chloride, auranofin and sodium aurothiomalate. Studies on a human epithelial cell line and its sub-strains made resistant to the antiproliferative effects of these gold compounds

The possible influence of gold(III) chloride and the two gold(I)-containing anti-arthritic drugs, auranofin and sodium aurothiomalate, on cellular ploidity and cell cycle progression was investigated on cultured human epithelial cells. Four different cell lines were used: the parent line (HE) and three sub-strains which previously had acquired resistance to the antiproliferative effects of either 350 mumol gold chloride/l culture medium (HEAu350), 2 mumol auranofin/l (HEAF) or 300 mumol sodium aurothiomalate/l (HEMyo). DNA-histograms were obtained by flow cytometry examinations during a 9-days' exposure to either of these gold-containing compounds and concentrations. The HE, HEAF and HEMyo cells had similar ploidities, close to tetraploid. The HEAu350 cells had altered ploidity to distinct tetraploid. The distribution of the resistant cells with the cell cycle phases was not different from that of untreated HE cells. The HE cells, when treated with auranofin or sodium aurothiomalate, accumulated in the G2-phase of the cell cycle. In addition, a new cedecoploid peak appeared. No such changes were observed on gold chloride exposure or in HE controls grown without drug supplement. The effects of auranofin and sodium aurothiomalate on cell cycle progression of the HE cells possibly indicate a tendency to polyploidity, and furthermore that inhibition of cellular mitosis is one mechanism of the antiproliferative effect common to the two drugs.