Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twelve non-steroidal anti-inflammatory agents (NSAI's) and one steroidal anti-inflammatory agent, dexamethasone, were examined in the carrageenan edema test (CET) in the rat and in the ultraviolet light-induced erythema test (UVE) in the guinea pig to evaluate the correlation between those models of inflammation and the clinical dose of the NSAI's in the treatment of rheumatoid arthritis. The regression of the logarithm of the clinical dose with the logarithm of the ED50 for UVE gave a slope of 0.54 implying a non-parallelism of assays and a difference in mechanism. Dexamethasone failed to inhibit the UVE thereby corroborating this point. The parallelism of the logarithm of the clinical dose with the logarithm of the ED50 for the CET was substantially better (slope = 0.86). Dexamethasone was active in CET and its dose would be predicted by the CET regression. When only one variable was used for a prediction, log(CET) was a better predictor of log (clinical dose) than log(UVE). Standard methods for best regression selection indicated that even when both predictor variables were considered, log(CET) alone gave the best regression equation for predicting clinical dose. The view that inhibition of prostaglandin biosynthesis is the primary anti-inflammatory mechanism of NSAI's in rheumatoid arthritis is discussed in terms of these findings.
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PMID:A comparison of the carrageenan edema test and ultraviolet light-induced erythema test as predictors of the clinical dose in rheumatoid arthritis. 47 3

A number of fibroblastoid synovial cell lines have been established from rheumatoid joints. These cell lines were shown to express the interleukin 6 (IL-6) gene constitutively, and exposure of these cells to 5 ng/ml of recombinant human interleukin 1 beta (IL-1 beta) increased IL-6 gene expression. Other recombinant human lymphokines, namely interferon-gamma, tumor necrosis factor-alpha, and granulocyte-macrophage colony stimulating factor had no enhancing effect on IL-6 gene expression. Dexamethasone added to the cultures at 10(-7) M concentration suppressed the constitutive expression of the IL-6 gene. At a concentration of 10(-5) M, dexamethasone partially suppressed the IL-1 enhanced expression of IL-6. The IL-6 gene probe also hybridized to RNA from unfractionated synovial fluid cells, peripheral blood T cells and non-T cells but not Epstein-Barr virus transformed peripheral blood B cells of patients with rheumatoid arthritis. Our results suggest that in rheumatoid arthritis, synovial fibroblasts actively participate in joint inflammation by lymphokine production. The coexpression of both IL-1 and IL-6 by one synovial fibroblast line suggests a mechanism for the perpetuation of synovitis.
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PMID:Expression of the interleukin 6 gene in rheumatoid synovial fibroblasts. 170 61

Interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) have been reported to contribute to the pathogenesis of many inflammatory diseases, e.g., rheumatoid arthritis. As monocytes are believed to be the primary source of these cytokines in peripheral blood, the present study was conducted to establish ranges and patterns of IL-1 beta and TNF-alpha secretion. Using heparinized unseparated whole blood obtained from normal human volunteers, peripheral blood monocytes were stimulated with Sal. minnesota LPS or BSA/anti-BSA immune complex-coated beads (BSA-beads). ELISAs for IL-1 beta and TNF-alpha were employed to quantitate cytokine levels in blood plasma without performing arduous and time-consuming extraction procedures. Over the course of a 6 hr incubation, LPS elicited a dose-dependent increase in TNF-alpha and IL-1 beta production. Preincubation of whole blood with interferon-gamma prior to the addition of a suboptimal dose of LPS or BSA-beads resulted in a synergistic potentiation of IL-1 beta/TNF-alpha production. Dexamethasone, utilized in the treatment of rheumatoid arthritis, proved to be a potent inhibitor of cytokine biosynthesis in whole blood ex vivo. The measurement of cytokine biosynthesis in a relevant physiologic environment not only avoids non-specific monocyte activation, but also may increase our ability to predict clinical outcomes in rheumatoid arthritis and/or other inflammatory diseases.
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PMID:Cytokine production in whole blood ex vivo. 179 50

A multicentre double-blind comparative trial was performed in 138 patients with rheumatoid arthritis (RA) after biweekly intravenous or intramuscular injections of liposteroid (containing 2.5 mg of dexamethasone), which had been developed as a drug for targeting therapy of RA, and Decadron (containing 3.3 mg of dexamethasone) as a reference drug. The results showed a tendency to a significantly higher rate of improvement with lower frequency of side-effects in the liposteroid group than in the Decadron group. This study indicates that liposteroid is more useful for RA and that the separation of the efficacy and side-effects of steroids could be clinically confirmed to some extent.
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PMID:Double-blind study with liposteroid in rheumatoid arthritis. 391 36

Iatrogenic osteoporosis is a very common secondary osteoporosis is found in patients treated with large dosage of glucocorticosteroid of long duration. Six cases listed in this article including 2 cases of bronchial asthma, 2 cases of bronchial asthma, 2 cases of rheumatoid arthritis, 1 case of skin disease and 1 case of callagenosis (three male patients and three female patients). The age is from 27-46. The duration of treatment of primary disease with glucocorticosteroid is 1 to 3.5 years, with the average of 1.56 years. With the exception of one case treated with Dexamethasone one of 0.75g daily, the other 5 cases are treated with predinisone of 5-30mg daily. After they treated with hormone every other day and added Calcium and vitamin D and followed up 1 year, the mineral contents in the bone of all 6 patients are increased and the biochemistry indexes are improved.
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PMID:[Iatrogenic osteoporsis: six case reports]. 771 9

Activated synoviocytes are major effector cells in the pathogenesis of rheumatoid arthritis (RA) because of their capacity to secrete a variety of inflammatory mediators. Among these mediators, the chemotactic proteins monocyte chemoattractant protein 1 (MCP-1) and interleukin 8 (IL-8) are likely to contribute to the recruitment of inflammatory cells into the arthritic joint. We examined the effects of anti-rheumatic drugs on the MCP-1 and IL-8 production by cultured RA synoviocytes exposed to pro-inflammatory agonists. Both chemotactic cytokines were quantified by specific enzyme-linked immunosorbent assays (ELISA), and found to accumulate in the culture supernatants. Although the time course of formation was similar, the yield of IL-8 was three to 10-fold higher than that of MCP-1. Non-steroidal anti-inflammatory drugs inhibited the synthesis of prostaglandins, but did not influence the production and release of both chemotactic cytokines. Of three disease-modifying drugs tested, dexamethasone and gold sodium thiomalate (GST) inhibited the production of IL-8 and MCP-1, while methotrexate (MTX) was inactive. Dexamethasone reduced the production of MCP-1 and IL-8 by 20-65% and 60-80%, respectively, whilst GST inhibited MCP-1 and IL-8 synthesis in suboptimally, but not in optimally stimulated synoviocytes. Taken together, these results show that the production of MCP-1 and IL-8 is similarly affected by anti-rheumatic drugs and that dexamethasone is the most potent inhibitor suggesting that part of the anti-rheumatic action of glucocorticoids is due to prevention of accumulation of chemotactic cytokines acting on neutrophils and monocytes.
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PMID:Monocyte chemoattractant protein 1 and interleukin 8 production by rheumatoid synoviocytes. Effects of anti-rheumatic drugs. 803 99

Tumour necrosis factor alpha (TNF alpha) has been reported to play a key role in the pathogenesis of sepsis and chronic inflammatory diseases, including rheumatoid arthritis and atherosclerosis, suggesting that agents which inhibit TNF alpha production may have therapeutic utility for the treatment of such conditions. Production of TNF alpha by LPS (lipopolysaccharide)-stimulated murine, rat and human heparinized blood was investigated. LPS (1-100 micrograms/ml) caused a similar concentration- and time-dependent stimulation of TNF alpha production by rat and human blood, achieving levels of 750-5000 U/ml (L929 bioassay) at 6 h. In contrast, TNF alpha production by LPS-stimulated murine blood was poor and variable (0-150 U/ml). Dexamethasone and pentoxifylline caused a concentration-dependent inhibition of TNF alpha production by LPS-stimulated human and rat blood with IC50s of 0.26 +/- 0.05 and 73.0 +/- 26.4 microM for human and 5.7 +/- 1.8 nM and 20.6 +/- 8.0 microM for rat blood, respectively. Therefore, LPS-stimulated rat and human, but not murine, blood are suitable systems for the detection and evaluation of inhibitors of TNF alpha production.
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PMID:Production of TNF alpha by LPS-stimulated murine, rat and human blood and its pharmacological modulation. 831 28

The mechanism by which glucocorticoids inhibit interleukin (IL)-1 and IL-6 formation in human monocytes and a promonocytic cell line activated by Escherichia coli lipopolysaccharide was analyzed. Dexamethasone (DEX) decreased levels of IL-1 alpha and IL-1 beta mRNAs in a dose-related fashion. The DEX-induced decrease in levels of IL-1 alpha and IL-1 beta mRNAs was abolished by the steroid receptor antagonist RU486. The levels of IL-1 alpha and IL-1 beta proteins within the cells and of IL-1 beta in the culture medium were decreased by DEX to comparable extents, so that DEX had no detectable effect on cytokine secretion. DEX did not influence lipopolysaccharide-induced transcription of the IL-1 beta gene in monocytes. However, DEX markedly decreased the stability of IL-1 beta mRNA, as shown both by steady state measurements and by pulse-labeling. DEX-induced instability of IL-1 beta mRNA required protein synthesis. DEX was also found to be a potent inhibitor of IL-1-induced expression of the IL-6 gene in connective tissue-type cells from the synovium of patients with rheumatoid arthritis. Inhibition of the formation of proinflammatory cytokines, including IL-1 beta and tumor necrosis factor-alpha, is a mechanism by which glucocorticoids exert anti-inflammatory effects. Inhibition by glucocorticoids of the expression of IL-1 alpha in antigen-presenting cells could decrease the capacity of the cells to stimulate the proliferation of T lymphocytes. This activity, as well as inhibition of the production and effects of IL-1 beta, including induced formation of IL-6 and of certain lymphokines, could explain the immunosuppressive effects of glucocorticoids.
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PMID:Inhibition by glucocorticoids of the formation of interleukin-1 alpha, interleukin-1 beta, and interleukin-6: mediation by decreased mRNA stability. 842 22

We have investigated the ability of cells derived from the human joint to generate nitric oxide (NO). Synovial fibroblasts, articular chondrocytes and osteoblasts were cultured from tissues of patients undergoing hip replacement surgery, and synovial fluid leucocytes were obtained from patients undergoing joint aspiration. There was little spontaneous generation of NO by any of the cells after culture, but synovial fibroblasts, articular chondrocytes and osteoblasts all produced large quantities of NO in response to a cytokine mix of interleukin (IL)-1 beta + tumour necrosis factor alpha (TNF alpha) + interferon (IFN gamma). Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed the presence of mRNA transcripts for the inducible isoform of NO synthase in cytokine-stimulated but not in unstimulated cells. In contrast, leucocytes from synovial fluid did not produce NO either spontaneously or after cytokine stimulation, and mRNA for inducible NO synthase (iNOS) was not detected in these cells even by nested PCR. There were significant differences in the regulation of NO production between chondrocytes and other cells. Only chondrocytes generated NO in response to IL-1 beta or TNF alpha alone, whereas synovial fibroblasts and osteoblasts required the presence of at least two cytokines to generate NO. Dexamethasone (10(-6)M) had a small but significant inhibitory effect on NO production by chondrocytes, synovial fibroblasts and osteoblasts. Our results indicate that several cells within the human joint have the potential to generate NO in the presence of an appropriate pro-inflammatory cytokine stimulus, while leucocytes in synovial fluid are not a significant source of NO. The data support suggestions that NO is produced within the inflamed joint in diseases such as rheumatoid arthritis.
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PMID:Nitric oxide production in cells derived from the human joint. 862 Feb 93

Increased levels of nitric oxide (NO) and prostaglandins (PG) are present in the synovial fluid from patients with rheumatoid arthritis and osteoarthritis. Interleukin-1 beta (IL-1) has been shown to induce the synthesis of both of these mediators. The present work was designed to study the interactions of NO and PGE2 synthesis induced by IL-1 in rat articular cartilage. Incubation of intact cartilage with IL-1 resulted in different dose response curves for NO and PGE2 synthesis. Two inhibitors of nitric oxide synthase N-monomethyl-L-arginine (L-NMMA) and L-N-iminoethylornithine, (L-NIO), abolished the IL-1-induced nitrite production but failed to have any influence on the PGE2 synthesis. Exogenous NO, produced by two chemically different NO-releasing compounds (SIN-1 and GEA 3175) had no effect on PGE2 synthesis in articular cartilage. Dexamethasone and ketoprofen inhibited IL-1 induced PGE2 production, while nitrite synthesis remained unaltered. Acetylsalicylic acid (ASA) reduced PGE2 synthesis and had a slight inhibitory action also on NO production. In conclusion, our results show, that IL-1 induces the synthesis of both PGE2 and NO in articular cartilage but these two inflammatory mediators are not mediating the synthesis of one another.
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PMID:Endogenous nitric oxide and prostaglandin E2 do not regulate the synthesis of each other in interleukin-1 beta-stimulated rat articular cartilage. 897 55


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