dinoprost and Arthritis--Rheumatoid

Suprofen is a new potent analgesic with antiinflammatory properties that appears to inhibit prostaglandin synthetase in a tissue-selective manner, having relatively little effect on the kidneys of experimental animals. The effects were studied of one week of treatment of rheumatoid arthritis patients with suprofen or ibuprofen on Na+ and K+ excretion, creatinine clearance, urinary enzymes that are markers for tubular damage, and urinary prostaglandins such as PGE2 and 6-keto PGF1 alpha (a stable metabolite of prostacyclin). Neither compound caused changes in renal function related to the week of treatment, but significant decreases in prostaglandins were observed: this change was fully reversible after discontinuation of the drug.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Dinoprost; Double-Blind Method; Female; Humans; Ibuprofen; Kidney; Male; Middle Aged; Phenylpropionates; Prostaglandins F; Random Allocation; Suprofen

Plasma and knee joint synovial fluid (SF) concentration of diclofenac sodium and its hydroxylated metabolites were measured after chronic dosing with the 100 mg polymer matrix formulation. Peak concentrations were reached in plasma and SF roughly after administration. Plasma concentrations then fell rapidly, but concentrations in SF were maintained for up to 25 h. The active metabolite was present in both fluids throughout the study period. The slow-release form showed a longer plasma/SF equilibration time than the conventional tablet had in a previous study. Prostaglandin E1 and F2 alpha concentrations were lower in the early post-dose period but did not correlate with drug concentrations.

Topics: Adult; Aged; Alprostadil; Arthritis, Rheumatoid; Delayed-Action Preparations; Diclofenac; Dinoprost; Humans; Hydroxylation; Male; Middle Aged; Prostaglandins F; Random Allocation; Synovial Fluid

Chondrocytes are one of the main cell types involved in rheumatoid inflammation, releasing mediators which add to cartilage destruction, bone damage and consequently disability. Current evidence suggests that serotonin 5-HT(3) receptor antagonists (5-HT(3)RA) show anti-inflammatory and antioxidant properties in vitro and in vivo. Yet, the mechanisms of the anti-inflammatory effects of 5-HT(3)RA have not been elucidated in detail.. Therefore, we examined in detail the effects of 5-HT(3)RA on inflammatory parameters in human primary chondrocytes in vitro by studying prostaglandin E2 (PGE2) and 8-isoprostane (8-iso-PGF2α) levels by EIA and interleukin-6 (IL-6) synthesis by ELISA. Cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) protein levels were analyzed by Western blot.. We found a significant reduction of IL-1β induced PGE2, 8-iso-PGF2β and IL-6 chondrocytes by 5-HT(3)RA especially by dolasetron.. This study provides additional support to the potential use of 5-HT(3)RAs as therapeutic agents to reduce joint inflammation.

Topics: Arthritis, Rheumatoid; Cells, Cultured; Chondrocytes; Cyclooxygenase 2; Dinoprost; Dinoprostone; Humans; Indoles; Interleukin-1beta; Interleukin-6; Intramolecular Oxidoreductases; Primary Cell Culture; Prostaglandin-E Synthases; Quinolizines; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists

Thromboxane (TX) biosynthesis by platelets and other cells in response to inflammatory triggers may provide a link between chronic inflammatory disease and atherothrombosis in rheumatoid arthritis (RA). In this study, we investigated the determinants of TX biosynthesis in RA, with particular reference to enhanced oxidative stress, receptor for advanced glycation end-products (RAGE) hyperactivity, and anti-tumor necrosis factor (TNF) treatment. Fifty-four patients with RA and 20 healthy subjects were recruited and a cross-sectional comparison of urinary 11-dehydro-TXB(2), 8-iso-PGF(2alpha), and plasma endogenous secretory RAGE (esRAGE) levels was performed between patients and controls. Urinary 11-dehydro-TXB(2) was significantly higher in RA patients than in healthy controls [425 (309-592) vs 233 (158-327) pg/mg creatinine, P<0.0001]. Furthermore, urinary 8-iso-PGF(2alpha) [323 (221-515) vs 172 (91-292) pg/mg creatinine, P<0.0001] and plasma esRAGE [155 (100-240) vs 377 (195-486) pg/ml, P=0.001] were higher and lower, respectively, in patients than in controls. A direct correlation was found between urinary 11-dehydro-TXB(2) and 8-iso-PGF(2alpha) only in patients not on anti-TNF therapy (r=0.420, P=0.021). Conversely, patients on anti-TNF therapy showed significantly lower urinary 8-iso-PGF(2alpha) [284 (201-373) vs 404 (241-539) pg/mg creatinine, P=0.043] but not 11-dehydro-TXB(2) than anti-TNF-treated subjects, with esRAGE as the only independent predictor of 11-dehydro-TXB(2) in this group of patients (adjusted R(2)=0.496, beta=-0.725, SEM=0.025, P=0.001). In conclusion, we provide biochemical evidence of enhanced TX biosynthesis in patients with RA, driven, at least in part, by lipid peroxidation. Treatment with anti-TNF agents may blunt isoprostane generation in the absence of significant effects on TX biosynthesis. We suggest that RAGE hyperactivity may escape TNF blockade, thus contributing to persistent TX biosynthesis in this setting.

Topics: Adult; Aged; Arthritis, Rheumatoid; Biomarkers; Case-Control Studies; Dinoprost; Female; Humans; Male; Middle Aged; Oxidants; Oxidative Stress; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Thromboxane B2; Thromboxanes

To explore the effects of FK506 on the inhibition by triptolide (TP) of cell proliferation and expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and their inducing products PGE2, NO in human rheumatoid arthritis synovial fibroblasts (RASF), and to study the mechanisms of combination of FK506 and TP in RA therapy, RASF used in the experiments were obtained from synovial tissue of patients with RA and were cultured. RASF were pretreated with FK506(10-1000 nmol/L)for 2 h, then the cells were stimulated with TNF alpha(20 microg/L) in the presence or absence of TP (10 microg/L). The RASF proliferation was determined by [(3)H]-TdR incorporation, and the productions of PGE2 and NO in culture supernatants of RASF were detected with competitive ELISA and enzyme reduction of nitrate. Expression of COX-2 and iNOS mRNA in RASF were analyzed by semi quantitative RT-PCR. Expressions of COX-2 and iNOS protein were estimated by Western blot method and cellular enzyme immunoassay in synovial fibroblasts. NF-kappa B activity in whole-cell extract of RASF was also measured by an ELISA-based method. Results showed that neither FK506 nor TP at lower concentration (10 microg/L) alone affected TNF alpha-induced COX-2, iNOS expression and production of PGE2, NO in synovial cells. Combined treatment of FK506 and a lower concentration of TP (10 microg/L) down-regulated COX-2 and iNOS mRNA and protein expression, and their inducing products PGE2 and NO of synovial fibroblasts. This effect was positively correlated with FK506 concentrations (10-1000 nmol/L). NF-kappa B activity in TNF alpha-stimulated synovial cells was suppressed more profoundly by FK506 plus TP (10 microg/L) treatment than those with TP (10 microg/L) alone. No change was observed in inhibition of proliferation of synovial cells after combined treatment of FK506 and TP. In conclusion, FK506 enhanced TP-mediated down-regulation of COX-2, iNOS and their inducing products PGE2, NO in human RASF by suppressing the activity of NF-kappa B.

Topics: Arthritis, Rheumatoid; Blotting, Western; Cell Division; Cells, Cultured; Cyclooxygenase 2; Dinoprost; Diterpenes; Enzyme-Linked Immunosorbent Assay; Epoxy Compounds; Fibroblasts; Gene Expression Regulation, Enzymologic; Humans; Immunosuppressive Agents; Isoenzymes; Membrane Proteins; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Phenanthrenes; Prostaglandin-Endoperoxide Synthases; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Synovial Membrane; Tacrolimus; Tumor Necrosis Factor-alpha

The content of cyclic nucleotides in blood plasma was measured in 151 patients suffering from rheumatoid arthritis. As compared to the control, the patients demonstrated a significant decrease of the cAMP content and a rise of the cGMP content. The disease standing was found to produce an appreciable effect on the cAMP content. RA patients untreated with glucocorticoids manifested significant correlations between the content of cyclic nucleotides and some characteristics of inflammation and of the immune status. At the same time the majority of such correlations may be lost under conditions of hormonal dependence, which is likely to attest to dysregulation of inflammatory process. In the course of the treatment, the content of cAMP in the plasma increase is attended by a reduction increases in 63.8% of the patients. In the majority of them, that of the level of circulating immune complexes, thereby supporting the relationship between immunopathological and metabolic disorders at the cellular level.

Topics: Antigen-Antibody Complex; Arthritis, Rheumatoid; beta 2-Microglobulin; Cyclic AMP; Cyclic GMP; Dinoprost; Epoprostenol; Humans; Immunoglobulin E; Prostaglandins E; Thromboxanes

Radioimmunoassay was used to study the content of prostaglandins in blood plasma of patients suffering from rheumatoid arthritis (PGE in 133 and PGF2 alpha in 102 patients). It has been established that as compared to the control group subjects, it is appreciably elevated and reflects the degree of inflammatory process activity, being pronounced to a greater measure in persons not receiving glucocorticoids than in hormone-dependent patients. A relationship has been revealed between the content of PGE and PGF2 alpha and certain clinical and laboratory characteristics (disease standing, intensity of exudative component of inflammation, the presence of humoral and cellular immunity disorders, anemia, and some visceral lesions), which may be of definite importance in the assessment of the patient's status. The time-course of changes in blood plasma prostaglandins reflects on the whole the dynamics of the disease activity, being related to a greater degree to the application of nonsteroidal antiinflammatory agents than of glucocorticoids.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Blood Sedimentation; Dinoprost; Female; Glucocorticoids; Humans; Male; Middle Aged; Prostaglandins E

Using stable-isotope techniques, we measured rates of quadriceps muscle protein synthesis in twelve women with sero-positive rheumatoid arthritis. The results were compared to those from the normal limb of seven women with unilateral osteoarthritis of the knee. Six patients had never received corticosteroid immuno-suppression, but the other six had taken an average of 8 mg Prednisolone per day for 9 years. Quadriceps atrophy was present in both sets of patients with rheumatoid arthritis (normal legs 444 +/- 182, rheumatoid 190 +/- 40, rheumatoid + steroid 300 +/- 110 micrograms protein/micrograms DNA, means +/- SD, both P less than 0.001). Muscle protein synthesis, calculated by comparing the incorporation of 13C-leucine into biopsy samples taken after an 8 h L-[1-13C] leucine infusion with the time averaged enrichment of blood alpha-ketoisocaproate, was 0.056 +/- 0.005% h-1 in the patients not receiving steroids compared with 0.050 +/- 0.02% h-1 in normals (P greater than 0.05) indicating that muscular atrophy was primarily due to an increase in rate of muscle protein breakdown. Intra-muscular PGE2 concentration was increased in these patients (rheumatoid 0.12 +/- 0.06 ng mg-1 tissue, normals 0.06 +/- 0.03 ng mg-1 tissue, P less than 0.05). Patients taking corticosteroids had a markedly depressed rate of muscle protein synthesis (0.035 +/- 0.008% h-1, P less than 0.05) and reduced intra-muscular PGF 2 alpha concentration (P less than 0.01). We conclude that steroid therapy significantly influences the mechanism of skeletal muscle atrophy in patients with rheumatoid arthritis.

Topics: Aged; Arthritis, Rheumatoid; Dinoprost; Female; Humans; Middle Aged; Muscle Proteins; Muscles; Muscular Atrophy; Prednisolone

To evaluate the role of prostanoids in rheumatoid arthritis the effects of anti-inflammatory drugs on prostanoid concentrations and their ratios were studied in a primary culture of adherent synovial cells from patients with rheumatoid arthritis. Cells from rheumatoid synovium have a great capacity for prostanoid production. PGE2 is the main prostanoid but synovial cells are also capable of producing 6-keto-PGF1 alpha and PGF2 alpha. There were also very low TxB2 concentrations in the culture medium after incubation. All nonsteroidal anti-inflammatory drugs used (diclofenac, indomethacin and tolfenamic acid) reduced markedly, in concentrations achieved therapeutically (greater than or equal to 0.13 mumol/l), the production of all the prostanoids from endogenous substrate. There were no differences in the efficacity of the drugs. Hydrocortisone was needed for higher concentrations to inhibit PGE2, 6-keto-PGF1 alpha and PGF2 alpha production. TxB2 formation remained almost unaltered. After the drug incubation there were also clear alterations in the ratios between these prostanoids, which may have therapeutic importance. It is suggested that this kind of synovial cell culture can be used for testing the effects and mechanisms of different anti-inflammatory drugs in standardized cell culture conditions.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Arachidonic Acids; Arthritis, Rheumatoid; Cells, Cultured; Dinoprost; Dinoprostone; Fatty Acids; Female; Humans; Hydrocortisone; Male; Middle Aged; Prostaglandins E; Prostaglandins F; Prostanoic Acids; Synovial Membrane; Thromboxane B2

The effect of D-penicillamine (DPA) on immunoreactive prostanoid concentrations was studied in a primary culture of adherent synovial cells from patients suffering from rheumatoid arthritis (RA). DPA in clinically achievable concentrations increased the levels of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) and reduced those of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) synthetized from endogenous substrate. The capacity for PGE2 and 6-keto-PGF1 alpha production in the presence of exogenous arachidonic acid was decreased by DPA. These effects may be connected with the antirheumatic and immunosuppressive action of DPA.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arthritis, Rheumatoid; Cells, Cultured; Dinoprost; Dinoprostone; Female; Humans; Male; Middle Aged; Penicillamine; Prostaglandins; Prostaglandins E; Prostaglandins F; Synovial Membrane; Thromboxane B2

There is known to be a significant correlation between the number of glucocorticoid receptors in tissues and their anti-inflammatory effect. In this work, the specific binding of glucocorticoids was studied in inflammatory fibroblasts. Human fibroblasts were obtained from the knee joint of a rheumatoid patient undergoing surgery; experimental fibroblasts were from rat granulomas. The same study was carried out in quiescent synovial fibroblasts from a healthy subject (post-traumatic amputation) and from rat subcutaneous conjunctive tissue. Fibroblasts were obtained by explant cultures and subcultures in monolayers. The stimulation state of cells was evaluated by the amounts of PGE2 and PGF2 alpha released into the culture media. Analysis of the proportions of steroid bound to whole cells showed evidence of specific glucocorticoid receptors in all fibroblasts. Their number was three times higher in cells from inflammatory tissues than from controls. This increased number of receptors in inflammatory cells could be the result of the action of one or more mediators that promote their biosynthesis.

Topics: Animals; Arthritis, Rheumatoid; Cells, Cultured; Connective Tissue; Dexamethasone; Dinoprost; Dinoprostone; Fibroblasts; Granuloma; Humans; Inflammation; Kinetics; Prostaglandins E; Prostaglandins F; Rats; Receptors, Glucocorticoid; Synovial Membrane

The efficacy of anti-inflammatory agents is related to their concentration in the peripheral compartments. In rheumatoid arthritis a drug's affinity for synovial tissue and synovial fluid is a decisive factor in treatment. The short-term efficacy of piroxicam was studied, relating the synovial concentration of prostaglandins and acid phosphatase and LDH to piroxicam synovial and plasma levels. After withdrawal of synovial fluid for pre-treatment measurements, 10 patients received 20 to 30 mg of piroxicam/day for eight days. The drug reached an average level of 3.56 +/- 0.9 micrograms/ml in synovial fluid, and 7.73 +/- 1.6 micrograms/ml in plasma. The acid phosphatase decreased from an initial average level of 29 mu/ml to a final average level of 15.999 mu/ml. The LDH showed an initial average level of 725.3 mu/ml and a final average of 471.2 mu/ml (p less than 0.01). The prostaglandin levels were quantified by two methods: indirectly, by measuring the malonilaldehyde concentration in nMol/ml, which showed an average level decrease of 48.75% in 100% of the cases; and directly, by means of thin layer chromatography and biological assay on rats' gastric fundus, against controls. The disappearance of PGE1 and a significant decrease in PGF2 alpha (100%) were observed. We conclude that piroxicam is an effective drug for the short-term treatment of rheumatoid arthritis. It penetrates rheumatoid synovial fluid, reaching 50% plasma concentrations. It has an anti-prostaglandin action, and could stabilize lysosomal membrane.

Topics: Acid Phosphatase; Adult; Alprostadil; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Dinoprost; Humans; L-Lactate Dehydrogenase; Middle Aged; Piroxicam; Prostaglandin Antagonists; Prostaglandins E; Prostaglandins F; Synovial Fluid; Thiazines

Topics: Arthritis, Rheumatoid; Diclofenac; Dinoprost; Humans; Indomethacin; Phenylacetates; Prostaglandin Antagonists; Prostaglandins E; Prostaglandins F; Synovial Fluid