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)

Synovial fibroblasts are likely to be a significant source of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte-CSF (G-CSF), which could be crucial to the pathogenesis of rheumatoid arthritis. Using specific enzyme-linked immunosorbent assays (ELISAs) and Northern analysis, GM-CSF and G-CSF expression were followed in human synovial fibroblast-like cells in response to a number of agents, either alone or in the presence of an optimal stimulatory concentration of interleukin-1 (IL-1). For both CSFs, interferon-gamma (100 U/mL) did not increase their levels but dramatically suppressed the stimulatory action of IL-1, while basic fibroblast growth factor (10(-8) mol/L), although nonstimulatory by itself, potentiated IL-1 action. The glucocorticoid, dexamethasone (10(-7) mol/L), inhibited IL-1-stimulated CSF production. However, evidence was obtained for noncoordinated CSF regulation. Cyclooxygenase inhibitors potentiated the action of IL-1 on GM-CSF synthesis but suppressed G-CSF synthesis, suggesting that endogenous cyclooxygenase products can have opposite effects in modulating the levels of each CSF. Also, the lymphokine, IL-4 (250 pmol/L), slightly inhibited GM-CSF formation in the presence of IL-1 but elevated the G-CSF levels in these cultures without having an effect by itself. Transforming growth factor beta (less than or equal to 20 ng/mL) did not modulate levels of either CSF. Mesenchymal cell production of both GM-CSF and G-CSF is generally viewed as being under coordinate control; our findings suggest that their synthesis in IL-1-stimulated human synoviocytes can be modulated by a number of agents, in some cases with divergent actions depending on which CSF is examined.
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PMID:Cytokine regulation of colony-stimulating factor (CSF) production in cultured human synovial fibroblasts. II. Similarities and differences in the control of interleukin-1 induction of granulocyte-macrophage CSF and granulocyte-CSF production. 137 87

Salicylates, at the high therapeutic doses used in the treatment of rheumatoid arthritis, produce an increase in ventilation and augment the carotid body reactivity to hypoxic stimulus, leading to an exaggerated hyperventilation during hypoxia. These effects had been related to the action of salicylates as uncouplers of oxidative phosphorylation. In the present study, carried out in an in vitro preparation of the rabbit carotid body, we show that acetylsalicylic acid and indomethacin, two anti-inflammatory drugs that are also powerful inhibitors of cyclooxygenase, the prostaglandin-synthetizing enzyme, produce an increase in the [3H]catecholamine release evoked by low oxygen stimulation. The drugs did not affect basal normoxic release, a finding that suggests that at the concentration used these anti-inflammatory agents do not have uncoupling actions, and that their effects on hypoxic-induced release of [3H]catecholamines is mediated by their specific action as cyclooxygenase inhibitors. In agreement with this suggestion we found that prostaglandin E2 completely prevented the effects of both anti-inflammatory agents. In addition, our data indicate that endogenously synthetized prostaglandins are powerful modulators of chemoreceptor cell function.
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PMID:Potentiation by cyclooxygenase inhibitors of the release of catecholamines from the rabbit carotid body and its reversal by prostaglandin E2. 140 87

The effect of combination NSAID therapy of tilomisole with aspirin or naproxen was studied in rats with carrageenan-induced paw edema and established adjuvant arthritis. Inflamed paws were measured using mercury plethysmography and the arthritic paws were X-rayed to determine any bony/soft tissue changes. The gastrointestinal tract was also examined for bleeding and ulceration. Tilomisole had a less potent acute anti-inflammatory effect than aspirin or naproxen, but produced no significant gastrointestinal damage. A significant reduction in anti-inflammatory activity was observed with the tilomisole/aspirin combination in acute inflammation. Only additive interactions were observed with the naproxen inhibition. In the established arthritis assay, a significant synergistic anti-inflammatory response, i.e. both inhibition of paw edema and bone erosion, was also observed with the 80 and 93% tilomisole/naproxen combinations. The gastric ulcerogenic effect of the combination paralleled its increased activity. The synergism between tilomisole and naproxen in this chronic arthritic model may be due to enhanced cyclooxygenase inhibitory activity. These drug interaction studies suggest possible interactions in human clinical trials of rheumatoid arthritis.
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PMID:Interaction studies of tilomisole, aspirin, and naproxen in acute and chronic inflammation with assessment of gastrointestinal irritancy in the rat. 141 94

Cytokines have been implicated in the regulation of eicosanoid synthesis and synovial cell proliferation. To further define these mechanisms, we have compared the effects of basic fibroblast growth factor and platelet-derived growth factor on cell growth, prostaglandin E2 (PGE2) production and phospholipase A2 enzyme activity in long-term cultures of synovial cells from rheumatoid arthritis (RA) patients capable of proliferating in serum-free medium. Compared with serum-free medium alone, RA synovial cell growth was significantly enhanced by adding either basic fibroblast growth factor (bFGF) or platelet-derived growth factor (PDGF) to the culture medium. Growing RA synovial cells for 14 days in serum-free medium plus bFGF caused them to spontaneously release significant amounts of PGE2, an effect not seen if cells were grown in serum-free medium alone, or serum-free medium plus PDGF. Enhanced release of PGE2 occurred when arachidonic acid was added to bFGF but not PDGF-treated RA synovial cells, suggesting that bFGF increased cyclooxygenase enzyme activity in these cells. Moreover, phospholipase A2 (PLA2) enzyme activity was found to be significantly greater in RA synovial cells grown for 14 days in serum-free medium containing bFGF alone, or bFGF plus interleukin 1 beta (IL-1 beta) compared with cells grown in either serum-free medium alone, or serum-free medium plus PDGF. Similarly, bFGF plus IL-1 beta-stimulated release of PLA2 activating protein, a novel mammalian phospholipase stimulator found in high concentrations in RA synovial fluid.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of synovial cell growth: basic fibroblast growth factor synergizes with interleukin 1 beta stimulating phospholipase A2 enzyme activity, phospholipase A2 activating protein production and release of prostaglandin E2 by rheumatoid arthritis synovial cells in culture. 142 Sep 99

One of the features of inflammation is increased oxygenation of arachidonic acid which is metabolized by two enzymic pathways--the cyclooxygenase (CO) and the 5-lipoxygenase (5-LO)--leading to the production of prostaglandins and leukotrienes respectively. Amongst the CO products, PGE2 and amongst the 5-LO products, LTB4 are considered important mediators of inflammation. More than 200 potential drugs ranging from non-steroidal anti-inflammatory drugs, corticosteroids, gold salts, disease modifying anti-rheumatic drugs, methotrexate, cyclosporine are being tested. None of the drugs has been found safe; all are known to produce from mild to serious side-effects. Ginger is described in Ayurvedic and Tibb systems of medicine to be useful in inflammation and rheumatism. In all 56 patients (28 with rheumatoid arthritis, 18 with osteoarthritis and 10 with muscular discomfort) used powdered ginger against their afflictions. Amongst the arthritis patients more than three-quarters experienced, to varying degrees, relief in pain and swelling. All the patients with muscular discomfort experienced relief in pain. None of the patients reported adverse effects during the period of ginger consumption which ranged from 3 months to 2.5 years. It is suggested that at least one of the mechanisms by which ginger shows its ameliorative effects could be related to inhibition of prostaglandin and leukotriene biosynthesis, i.e. it works as a dual inhibitor of eicosanoid biosynthesis.
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PMID:Ginger (Zingiber officinale) in rheumatism and musculoskeletal disorders. 149 22

A range of 12 non-steroidal anti-inflammatory drugs (NSAIDs), including members from each of the main chemical groups, were examined for their effects on the oxidative burst induced by the receptor stimulus, platelet-activating factor, and the two post-receptor stimuli, fluoride and dioctanoylglycerol. It was found that the NSAIDs fell into three categories: (1) those that increased the stimulated superoxide (O2-) response, (2) those that had no effect and (3) those that decreased O2- production. All the drugs were without effect in unstimulated cells. The mode of action of those drugs that caused enhancement of the O2- response is unlikely to be due to an inhibition of the cyclooxygenase pathway of arachidonate metabolism as not all NSAIDs caused the enhancement. This data could have clinical implications for the therapy of inflammatory disorders such as rheumatoid arthritis, in that those NSAIDs which cause an increased O2- response, while providing temporary relief of symptoms, could be exacerbating the underlying inflammatory condition and associated tissue damage.
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PMID:Cyclooxygenase-independent effects of non-steroidal anti-inflammatory drugs on the neutrophil respiratory burst. 154 Jan 98

The effects of sulfasalazine (SASP) and its metabolites sulfapyridine (SP) and 5-aminosalicylic acid (5-ASA) were investigated on release of prostaglandins (PG) and leukotrienes (LT) from synovial tissue of 37 patients with osteoarthritis, chondrocalcinosis and rheumatoid arthritis. Calcium ionophore A23187 significantly increased the release of PGE2, 6-keto-PGF1 alpha, LTB4, and LTC4 from human synovial tissue irrespective of the underlying joint disease. SASP inhibited release of LTC4 and increased release of PGE2. On the other hand, 5-ASA and SP inhibited the release of all eicosanoids measured. The effective concentrations of SASP and SP were found to be in the range which can be reached during SASP therapy. On the other hand, blood and synovial fluid levels of 5-ASA are considerably lower than those which inhibit eicosanoid synthesis in vitro. While nonsteroidal anti-inflammatory drugs, which are used for symptomatic therapy of rheumatoid arthritis, inhibit cyclooxygenase only, SP, the active metabolite of the second line anti-rheumatic drug SASP, inhibits both PG and LT release. Inhibition of LT synthesis by SASP and SP could contribute to the second line efficacy of SASP therapy in rheumatoid arthritis.
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PMID:[Effect of sulfasalazine and its metabolites on prostaglandin and leukotriene liberation from human synovial tissue]. 167 14

A 64-year-old woman with a 15-years-history of rheumatoid arthritis developed generalized hemorrhagic diathesis. Routine coagulation tests revealed a slightly diminished platelet count only. Platelet aggregation in vitro induced by ADP, collagen, thrombin, arachidonic acid and ristocetin were reduced. The patient's plasma aggregating activity was significantly diminished which was due to a decrease of the intraplatelet nucleotide pool. The number of mepacrine labelled bodies as well as dense bodies in electron microscopy was below the normal values as well. Moreover, the intraplatelet concentration of cyclooxygenase--malonylodialdehyde (MDA) and lipoxygenase pathway products were lowered. Total platelet immunoglobulin G and M contents were significantly increased. The platelet survival time (in vitro aspirin method) was slightly shortened. Finally the diagnosis of delta-acquired platelet storage pool deficiency (delta-SPD) was established and possibilities of treatment were discussed.
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PMID:[Acquired platelet storage pool deficiency in rheumatoid arthritis]. 178 43

Fish oil is rich in the polyunsaturated N-3 fatty acids, eicosapentaenoic (EPA) and docosahexaenoic acids (DCHA). EPA competes with arachidonic acid (AA) for metabolism by the cyclooxygenase and lipoxygenase pathways. Selective metabolites derived from EPA have reduced biological activities as compared with the AA-derived counterparts. Dietary supplementation with EPA led to incorporation of EPA into membrane phospholipids, an inhibition of 5-lipoxygenase pathway activity, and a reduction of the elaboration of platelet-activating factor. Neutrophil chemotaxis and the capacity of these cells to adhere to endothelial cells are substantially attenuated. This suggests that EPA has anti-inflammatory potential. Clinical trials in rheumatoid arthritis, psoriasis, atopic dermatitis, and bronchial asthma have shown beneficial effects. Whether the benefit obtained clinically is sufficient to replace or significantly reduce any clinical condition remains to be answered.
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PMID:Effects of dietary fish oil lipids on allergic and inflammatory diseases. 195 66

Agents used to treat rheumatoid arthritis were examined for their ability to modify synovial fluid phospholipase A2 (SF-PLA2) activity. Nonsteroidal or steroidal antiinflammatory drugs and disease modifying agents exhibited little or no PLA2 modulatory activity. The exceptions include weak inhibition displayed by the cyclooxygenase inhibitors, indomethacin (IC50 = 144.8 microM) and sulindac sulfide (30.2 microM) and a 5-lipoxygenase translocation inhibitor, MK-886 (IC50 = 50 microM). Cyclosporine potentiated acylhydrolysis (EC50 = 1.5 microM) whereas the other immunomodulators examined demonstrated no significant effect on SF-PLA2 activity. Our data show that there are no selective PLA2 inhibitors currently used in the treatment of human arthritic disease and the viability of this novel approach remains to be tested.
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PMID:Evaluation of antirheumatic drugs for their effect in vitro on purified human synovial fluid phospholipase A2. 202 1


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