thromboxane-b2 and Arthritis--Rheumatoid

Marine-derived n-3 polyunsaturated fatty acids (PUFA) may have a beneficial effect on inflammation via lowering pro-inflammatory eicosanoid concentrations. We aimed to assess the effect of marine-derived n-3 PUFA on prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and leukotriene B4 (LTB4) through systematic review and meta-analysis of randomized controlled trials.. A structured search strategy on PubMed, Web of Science and Cochrane up to November 2015 was undertaken in this meta-analysis. Standard mean difference was used to calculate the effect size of marine-derived n-3 PUFA on PGE2, TXB2 and LTB4 in a random-effect model. A total of 18 RCTs with 826 subjects were included in this systematic review and meta-analysis. Supplementation of marine-derived n-3 PUFA significantly decreased concentrations of TXB2 in serum/plasma in subjects with high risk of cardiovascular diseases (SMD:-1.26; 95% CI: -1.65, -0.86) and LTB4 in neutrophils in unhealthy subjects (subjects with non-autoimmune chronic diseases or auto-immune diseases) (SMD:-0.59: 95% CI: -1.02, -0.16). Subgroup analyses showed a significant reduction of LTB4 in subjects with rheumatoid arthritis (SMD: -0.83; 95% CI: -1.37, -0.29), but not in non-autoimmune chronic disease patients (SMD: -0.33; 95% CI: -0.97, 0.31). No significant publication bias was shown in the meta-analysis.. Marine-derived n-3 PUFA had a beneficial effect on reducing the concentration of TXB2 in blood of subjects with high risk of CVD as well as LTB4 in neutrophils in unhealthy subjects, and that subjects with RA showed lower LTB4 content with supplementation of marine-derived n-3 PUFA.

Topics: Anti-Inflammatory Agents; Arthritis, Rheumatoid; Chronic Disease; Dietary Supplements; Dinoprostone; Dose-Response Relationship, Drug; Eicosanoids; Fatty Acids, Omega-3; Fish Oils; Humans; Leukotriene B4; Randomized Controlled Trials as Topic; Research Design; Thromboxane B2; Treatment Outcome

The alterations in the metabolism of arachidonic acid to prostaglandin I2 (prostacyclin), a vasodilator antiaggregatory substance, and thromboxane A2, a vasoconstrictor proaggregatory substance, in diabetes mellitus are reviewed in this article. When tested in vitro, platelet aggregation is enhanced in some patients with diabetes mellitus. The synthesis of thromboxane B2, the stable metabolite of thromboxane A2, by platelets is increased in patients with diabetes mellitus compared with control subjects. This increased synthesis appears to play a role in the enhanced platelet aggregation since the latter can be reversed by aspirin treatment and in vitro by the thromboxane receptor-antagonist 13-azaprostanoic acid. Vascular prostacyclin synthesis is decreased in both patients and experimental animals with diabetes mellitus. Treatment of experimental animals with insulin reverses the decreased synthesis of prostacyclin. The etiology of the altered arachidonic acid metabolism remains uncertain but appears to be multifactorial and includes alterations in metabolic control and circulating immune complexes. The increased ratio of thromboxane A2 to prostacyclin, which favors an enhanced thrombotic state, may play a role in the accelerated vascular disease of diabetes mellitus.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Arthritis, Rheumatoid; Aspirin; Blood Platelets; Diabetes Mellitus; Epoprostenol; Humans; Insulin; Platelet Aggregation; Thromboxane A2; Thromboxane B2

An exposure-response model was used to characterize the pharmacokinetic-pharmacodynamic relationship of GW406381, a COX-2 inhibitor, based on data from ex vivo prostaglandin E2 inhibition collected in a phase 1 study in healthy subjects. The final model was then used to simulate a proof-of-concept study and to explore suitable dosing ranges in case of hepatic dysfunction or metabolic induction. Trough concentrations in the range of IC80 to IC95 were used as target therapeutic concentrations. Symptom relief in a subsequent phase 2b study in 400 patients with rheumatoid arthritis receiving GW406381 was then analysed to support the design of a phase 3 study in which doses in the range between 10 to 400 mg were explored. The exercise also allowed the evaluation of correlations between the biomarker and clinical end point. A 2-compartment model described the pharmacokinetics of GW406381, whereas the pharmacodynamics was described by an Imax model. In patients with normal organ function, the predicted median therapeutic dose was between 100 and 150 mg. The time course of symptom relief was fitted by a Weibull model, with an Imax model describing the drug effect. Simulations showed that dose-response discrimination occurred at doses higher than 150 mg, with predicted 60%-80% target engagement in the dose range of 150-400 mg.

Topics: Arthritis, Rheumatoid; Biomarkers; Computer Simulation; Cyclooxygenase 2 Inhibitors; Dinoprostone; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Male; Models, Biological; Pyrazoles; Pyridazines; Thromboxane B2

Interaction with platelet function by non-steroidal anti-inflammatory drugs (NSAIDs) is related to the inhibition of cyclo-oxygenase-1 (COX-1). In patients with rheumatoid arthritis (RA), only one of the COX-2-selective NSAIDs (nabumetone) has been demonstrated to spare platelet function partially.. To compare the effects of the COX-2-selective inhibitor, meloxicam, with those of the non-selective NSAID, naproxen, on platelet function and thromboxane levels in RA patients.. In this randomized, controlled, cross-over trial, 10 RA patients used meloxicam 7.5 mg bid and naproxen 500 mg bid, each during a 2-week period. Washout periods were applied. Before and after each 2-week period of NSAID intake, laboratory studies were performed.. Platelet aggregation was significantly less influenced, thromboxane levels were less inhibited (246 vs 117 pg/ml) and bleeding times were less prolonged with meloxicam than with naproxen (3.2 vs 2.3 min). Moreover, the results of all tests during meloxicam exposure were comparable with baseline values.. In RA patients, meloxicam, a representative of the selective COX-2 inhibitors, does not interfere with platelet function and thromboxane levels, in contrast with naproxen (a non-selective COX inhibitor).

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Bleeding Time; Blood Platelets; Cross-Over Studies; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Female; Humans; In Vitro Techniques; Male; Meloxicam; Middle Aged; Naproxen; Platelet Aggregation; Random Allocation; Thiazines; Thiazoles; Thromboxane B2

To investigate the efficacy and safety of SC-58635 (celecoxib), an antiinflammatory and analgesic agent that acts by selective cyclooxygenase 2 (COX-2) inhibition and is not expected to cause the typical gastrointestinal (GI), renal, and platelet-related side effects associated with inhibition of the COX-1 enzyme.. Four phase II trials were performed: a 2-week osteoarthritis efficacy trial, a 4-week rheumatoid arthritis efficacy trial, a 1-week endoscopic study of GI mucosal effects, and a 1-week study of effects on platelet function.. The 2 arthritis trials identified SC-58635 dosage levels that were consistently effective in treating the signs and symptoms of arthritis and were distinguished from placebo on standard arthritis scales. In the upper GI endoscopy study, 19% of subjects receiving naproxen (6 of 32) developed gastric ulcers, whereas no ulcers occurred in subjects receiving SC-58635 or placebo. The study of platelet effects revealed no meaningful effect of SC-58635 on platelet aggregation or thromboxane B2 levels, whereas aspirin caused significant decreases in 2 of 3 platelet aggregation measures and thromboxane B2 levels. In all 4 trials, SC-58635 was well tolerated, with a safety profile similar to that of placebo.. SC-58635 achieves analgesic and antiinflammatory efficacy in arthritis through selective COX-2 inhibition, without showing any evidence of 2 of the toxic effects of COX-1 inhibition associated with nonsteroidal antiinflammatory drugs.

Topics: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Aspirin; Celecoxib; Cyclooxygenase Inhibitors; Endoscopy; Female; Humans; Knee Joint; Male; Middle Aged; Naproxen; Osteoarthritis; Platelet Aggregation; Platelet Aggregation Inhibitors; Pyrazoles; Safety; Severity of Illness Index; Stomach Ulcer; Sulfonamides; Thromboxane B2; Treatment Outcome

A range of functional, biochemical, and psychological indicators was used to test the concept of "responders"/"nonresponders" and to seek predictors of response to 2 nonsteroidal antiinflammatory drugs in 9 patients with rheumatoid arthritis (RA) and 11 with osteoarthritis (OA).. In a balanced, randomized, double-blind, latin-square study design that involved four 4-week treatment periods, patients received ketoprofen or piroxicam (each for 2 of the 4 periods). Clinical and laboratory responses (pain, tenderness, swelling, patient and physician global assessments, acute-phase protein levels, and disability) were assessed in the last 2 weeks of each period. Responders were those who showed >30% improvement in at least 5 of 7 measures of disease activity. Mood was also assessed.. At baseline, variables were higher in RA than in OA patients. The drugs produced clear improvements in patients' visual analog scale scores, physicians' overall assessments, and patients' responses to the McGill Pain Questionnaire, as well as plasma prostaglandin concentrations. In patients with either RA or OA, responders could be distinguished from nonresponders; about one-third of patients were unambiguous responders. In RA, there were responder/nonresponder differences in lymphocyte counts, erythrocyte sedimentation rate (ESR), and levels of tumor necrosis factor alpha, but no differences were seen in OA patients. However, caution in interpretation of the data is necessary because of the small number of patients. Responders had improved mood scores compared with nonresponders in both disease groups. Baseline ESR and white blood cell counts were correlated with responder status in RA patients.. This study provides support for the responder/nonresponder concept. It also indicates that in RA, pretreatment ESR and lymphocyte counts are possibly useful indicators of therapeutic response.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Blood Sedimentation; Cross-Over Studies; Double-Blind Method; Female; Humans; Ketoprofen; Lymphocyte Count; Male; Middle Aged; Osteoarthritis; Piroxicam; Receptors, Interleukin-2; Thromboxane B2; Tumor Necrosis Factor-alpha

1. Single oral doses of 100 mg racemic ketoprofen were given to 15 patients (age range: 51-79 years) with rheumatoid arthritis and a range of creatinine clearances (CLCR) from 26 to 159 ml min-1. 2. The fractions unbound of (R)- and (S)-ketoprofen in plasma were determined for each subject after in vitro addition of rac-ketoprofen (enantiomer range: 1.00-6.00 micrograms ml-1) to pre-dose plasma. 3. An index of the antiplatelet effect of ketoprofen in vitro was measured as inhibition of platelet thromboxane B2 (TXB2) generation during the controlled clotting of whole blood (pre-dose) spiked with rac-ketoprofen. 4. In vivo studies revealed significant associations (P < 0.05) between the reciprocal of AUC for both unbound and total (bound plus unbound) (S)-ketoprofen and CLCR. Corresponding relationships were also observed for the (R)-enantiomer of ketoprofen. In addition, the half-life of each enantiomer was negatively correlated with CLCR. There was a positive relationship between the 24 h urinary recovery of combined non-conjugated and conjugated (R)-ketoprofen and CLCR while that for the (S)-stereoisomer failed to reach statistical significance (P > 0.05). 5. There was no difference between AUC for (R)- and (S)-ketoprofen for either unbound or total drug. 6. The mean +/- s.d. percentage unbound of (S)-ketoprofen in plasma (0.801 +/- 0.194%) exceeded (P < 0.05) the corresponding value for its optical antipode (0.724 +/- 0.149%). The percentage unbound of the (S)-enantiomer was higher at 6.00 micrograms ml-1 than that at enantiomer concentrations of 3.50 micrograms ml-1 and below, where it was invariant. The percentage unbound of (R)-ketoprofen was independent of plasma concentration up to 6.00 micrograms ml-1. There were no correlations between the percentage unbound of each enantiomer and either serum albumin concentration or CLCR. 7. The relationship between the serum concentration of unbound (S)-ketoprofen and the percentage inhibition of platelet TXB2 generation was described by a sigmoidal Emax equation for each patient. There was no correlation between the unbound concentration of (S)-ketoprofen in serum required to inhibit platelet TXB2 generation by 50% (EC50) and CLCR. The mean +/- s.d. EC50 was 0.216 +/- 0.143 ng ml-1. 8. These data indicate that diminished renal function is associated with an increased exposure to unbound (S)-ketoprofen, presumably due to regeneration of parent aglycone arising from the hydrolysis of accumulated acyl-glucuronid

Topics: Administration, Oral; Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Blood Platelets; Blood Proteins; Female; Humans; Ketoprofen; Kidney; Kidney Function Tests; Male; Middle Aged; Molecular Conformation; Structure-Activity Relationship; Thromboxane B2

The pharmacokinetics of flurbiprofen (Ansaid Tablets, Upjohn Company of Canada, Don Mills, Ontario) were evaluated in both younger (40 to 60 years) and elderly (65 to 83 years) rheumatoid arthritic patients after both a 100-mg single-dose administration and at steady state during a 100-mg twice-a-day dosage regimen. Both flurbiprofen plasma concentration-time profiles and the urinary excretion of flurbiprofen and its major metabolites were evaluated. The results indicate that the pharmacokinetics of flurbiprofen are linear in both age groups based on only minor changes between single-dose and steady-state parameter determinations and the agreement between calculated and predicted accumulation values in plasma concentrations. Only minor differences in the pharmacokinetic parameters were observed between the younger and elderly patients. Only free flurbiprofen clearance was found to have a significant but variable correlation to patient age. The effect of flurbiprofen on the urinary excretion of two prostaglandins were also evaluated throughout this study. In both age groups, the maximum decrease in urinary excretion was observed after the first dose, and this effect was maintained throughout the remainder of the study. Percent decreases from baseline in urinary excretion during drug administration were similar for both age groups. Similar side-effect profiles were observed between age groups.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Age Factors; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Body Weight; Female; Flurbiprofen; Humans; Male; Metabolic Clearance Rate; Middle Aged; Prospective Studies; Thromboxane B2

The synthesis of gastric and duodenal mucosal prostaglandin E2, prostaglandin I2, and thromboxane B2 during a 60 minute incubation of biopsy specimens, the degree of endoscopic and histological damage, and the anti-inflammatory response were all studied after a four week, double blind study of therapeutic doses of two non-steroidal anti-inflammatory drugs, naproxen and etodolac, received by 27 patients with active rheumatoid arthritis (13 receiving naproxen, 14 etodolac). Prostaglandin values after treatment did not differ from the baseline levels when all the patients were analysed as one group. Subgroup analysis showed that naproxen suppressed gastric prostaglandin E2 from a median of 29 to 9 ng/mg protein, duodenal prostaglandin E2 from 34 to 11 ng/mg, and duodenal prostaglandin I2 from 62 to 15 ng/mg protein. No overall suppression occurred with etodolac. Also, on the second assessment patients receiving naproxen had lower gastric and duodenal prostaglandin E2 and prostaglandin I2, but higher values of duodenal thromboxane B2, than patients receiving etodolac. Both drugs had comparable anti-arthritic activity and caused microscopic gastritis in similar proportions of patients. No correlation was detected between prostaglandin values and the mucosal damage which developed in seven patients receiving naproxen (54%) and three receiving etodolac (21%). These findings indicate that, unlike naproxen, etodolac does not seem to affect gastric or duodenal prostaglandin synthesis; other mechanisms of injury need to be considered.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Clinical Trials as Topic; Dinoprostone; Double-Blind Method; Duodenum; Epoprostenol; Etodolac; Female; Gastric Mucosa; Humans; Indoleacetic Acids; Intestinal Mucosa; Male; Middle Aged; Naproxen; Prospective Studies; Prostaglandins; Thromboxane B2

Etodolac has been shown to have a favorable safety profile in short-term and long-term studies in both osteoarthritis (OA) and rheumatoid arthritis (RA). Two studies were conducted to further assess the gastrointestinal (GI) safety profile of this drug. These studies were designed to compare the therapeutic efficacy and upper GI effects of etodolac (600 mg/day) and naproxen (1000 mg/day) administered over 4 weeks in patients with active rheumatoid arthritis. In addition, the relative effects of the drugs on prostaglandin levels in the stomach and duodenum were assayed in one study. Fifteen patients were included in each study and received either 300 mg b.i.d. of etodolac or 500 mg b.i.d. of naproxen. In both studies, endoscopic examinations were performed on day 1 of the study and again 4 weeks later. In the second study, at the time of each endoscopy, samples of gastric and duodenal mucosa were taken for histologic study and prostaglandin assay. Endoscopy results from the first study showed significant differences in favor of etodolac between the two treatment groups. In the second study more naproxen-treated patients had abnormal endoscopy results than did etodolac-treated patients. Results from prostaglandin assays in gastric and duodenal mucosa showed no overall suppression of gastric or duodenal prostaglandin levels for etodolac-treated patients in contrast to naproxen-treated patients, who showed suppression of PGE2 and PGI2. The results of these studies show that etodolac therapy caused less gastric and duodenal injury than naproxen and also support the theory that the GI safety of etodolac may be due to selective sparing of cytoprotective prostaglandins.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Dinoprostone; Dose-Response Relationship, Drug; Duodenum; Endoscopy; Epoprostenol; Etodolac; Female; Gastric Mucosa; Humans; Indoleacetic Acids; Male; Middle Aged; Mucous Membrane; Naproxen; Osteoarthritis; Patient Compliance; Prostaglandins; Stomach; Thromboxane B2; Time Factors

In a pilot study, 26 rheumatoid arthritic patients taking continuous, stable dosage regimens of nonsteroidal anti-inflammatory drugs and with developed gastric and duodenal lesions were administered sucralfate 1 g four times per day (14 patients) or cimetidine 400 mg twice daily (12 patients) in a single-blind regimen for six weeks. Eleven of the patients given sucralfate and eight of the patients taking cimetidine had improved lesion scores. The lesion score of 10 of the 14 patients taking sucralfate and four of the 12 patients taking cimetidine improved by 50 percent or better (not significant). The antrum and body of the gastric mucosa and the mucosa of the duodenum synthesized prostanoids and thromboxane A2, and there was no significant difference in the synthesis of individual prostanoids at entry to the trial in the groups assigned to sucralfate or cimetidine. After six weeks of administration of sucralfate, prostaglandin E2 (PGE2) synthesis by the antrum and body, but not the duodenum, was significantly greater than observed in the biopsy specimens at entry despite continuation of non-steroidal anti-inflammatory drug therapy. After six weeks of cimetidine treatment, no change in PGE2 synthesis was noted in any biopsy specimens when compared with the synthesis at entry. No change in the synthesis of PGF2 alpha, 6-oxo-PGF1 alpha, or thromboxane B2 was noted in gastric or duodenal biopsy specimens in any treatment group. Sucralfate and cimetidine administration resulted in improved gastroduodenal lesion scores in rheumatoid arthritic patients continuing with nonsteroidal anti-inflammatory drug therapy.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Cimetidine; Duodenum; Female; Gastric Mucosa; Humans; Intestinal Mucosa; Male; Middle Aged; Peptic Ulcer; Pilot Projects; Prostaglandins; Random Allocation; Sucralfate; Thromboxane B2

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

Omega-3 (omega-3) fatty acid rich-fish oil (FO) and vitamin E (vit-E) may delay the progress of certain autoimmune diseases. The present study examined the mechanism of action of omega-3 and omega-6 lipids and vit-E on the serum cytokines and lipid mediators in autoimmune-prone MRL/lpr mice (a model for rheumatoid arthritis, RA). The lpr (lymphoproliferative) gene is overexpressed in these mice causing extensive lymphoproliferation, lupus-like symptoms and accelerated aging.. Weanling female MRL/lpr and congenic control MRL/++ mice were fed 10% corn oil (CO, omega6) or FO-based semipurified diets containing two levels of vitamin E (vit-E-75, I.U. and vit-E-500 I.U./Kg diet) for four months. At the end of the experiment, serum anti-DNA antibodies, cytokines and lipid mediators levels were determined.. The appearance of enlarged lymph nodes was delayed in the mice fed FO, and the FO-500 IU vit-E diet offered further protection against enlargement of lymph nodes. The MRL/lpr mice exhibited significantly higher levels of serum anti-dsDNA antibodies. The FO-fed mice had significantly lower serum IL-6, IL-10, IL-12, TNF-alpha, PGE2, TXB2 and LTB4 levels compared with CO-fed mice. In mice fed 500 IU vit-E diets, the serum IL-6, IL-10, IL-12 and TNF-alpha levels were significantly lower and serum IL-1beta was significantly higher compared to 75 IU-vit-E-fed mice in CO/FO or both. The levels of anti-DNA antibodies, IL-4, IL-6, TNF-alpha, IL-10 and IL-12 were higher in the sera of MRL/lpr mice. The FO diet lowered the levels of these cytokines (except IL-4) and lipid mediators. Adding 500 IU of vit-E to the FO diet further lowered the levels of IL-6, IL-10, IL-12, and TNF-alpha.. It is clear from our observations that the beneficial effects of FO can be enhanced by the addition of 500 IU of vit-E in the diet. The FO diet containing 500 IU of vit-E may specifically modulate the levels of IL-6, IL-10, IL-12 and TNF-alpha and thereby may delay the onset of autoimmunity in the MRL/lpr mouse model. The observations from this study may form a basis for selective nutrition intervention based on specific fatty acids and antioxidants in delaying the progress of RA.

Topics: Animals; Antibodies, Antinuclear; Arthritis, Rheumatoid; Body Weight; Cytokines; Dietary Fats, Unsaturated; Dinoprostone; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Female; Interleukins; Kidney; Leukotriene B4; Mice; Thromboxane B2; Tumor Necrosis Factor-alpha; Vitamin E; Weaning

To explore the therapeutic mechanism of Shuguan Granule (SGG) in treating mid-late rheumatoid arthritis.. Based on the principle of reinforcing Kidney to treat arthritis, removing phlegm to remove stasis, two SGG, Shuguan Wenjing granule (SW) and Shuguan Qingluo granule (SQ) were prepared and used to treat mid-late 44 and 43 patients of rheumatoid arthritis respectively. The clinical result was compared with that of Wangbi Granule. Animal experiments on the effect of the two SGG were conducted.. The total effective rate of the SW, SQ and control group was 88.64%, 93.02% and 73.17% respectively. Results of experimental studies in rats with adjuvant-induced arthritis showed that the two SGG obviously raise the level of serum SOD, and lowered the levels of serum interleukin-1, plasma prostaglandin E2 and thromboxane B2, as compared with the model group, the difference was significant (P < 0.05, P < 0.01).. The two SGG have a comprehensive function of anti-inflammatory, analgesia, antioxidation, antihypercoagulation and immunoregulation.

Topics: Adult; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Drugs, Chinese Herbal; Female; Humans; Immunoglobulin G; Interleukin-1; Male; Middle Aged; Random Allocation; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Thromboxane B2

Clinical and experimental evidence suggests that arachidonic acid metabolism through lipoxygenase and cyclooxygenase pathways may play an important role in the pathogenesis of both inflammatory and degenerative joint diseases. The aim of the present paper was to measure the levels of different arachidonate metabolites in arthrosis or rheumatoid joint effusions.. We studied synovial fluids from 22 patients with arthrosis and 8 patients with rheumatoid arthritis. The levels of TxB2, 6-keto-PGF1 alpha LTB4 and LTC4 were measured by radioimmunoassay.. The levels of the different arachidonate metabolites were higher in patients with rheumatoid arthritis than in those with arthrosis and the differences were always statistically significant, except for TxB2 values. Furthermore, in patients with arthrosis the levels of such metabolites were not significantly correlated with one another, with the exception of LTB4 and LTC4 values, while in patients with rheumatoid arthritis these levels were directly and significantly correlated.. In inflammatory joint disease levels of arachidonate metabolites are higher and more directly correlated with one another than in degenerative joint disease. Our data may explain the better efficacy of non-steroidal anti-inflammatory drugs in patients with arthrosis than in those with rheumatoid arthritis and the frequent necessity for steroidal treatment in this last condition.

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acid; Arthritis, Rheumatoid; Humans; Joint Diseases; Leukotriene B4; Leukotriene C4; Radioimmunoassay; Synovial Fluid; Thromboxane B2

Twelve patients suffering from rheumatoid arthritis and having swollen knees were treated with 1.1 g/day of sodium naproxen administered in one dose, daily for 5 days. The 72-h wash-out period was verified by the absence of any nonsteroidal anti-inflammatory drug using a HPLC screening. Blood and synovial fluid samples were drawn just before treatment and 24 h after the last dose. Eicosanoids (PGE2, 6-keto-PGF1 alpha, TXB2, LTB4, LTC4) in synovial fluid were determined by immunoenzymatic assays. In plasma and synovial fluid, hyaluronic acid was assayed by radiometric assay and sodium naproxen by HPLC. Free drug was determined by equilibrium dialysis. Statistical analysis used nonparametric tests. Pain relief (evaluated on a visual scale), morning stiffness, and scores on the Lee and Ritchie indices all decreased significantly, as did PGE2 and LTB4 concentrations. The decrease in 6-keto-PGF1 alpha and TXB2 was not significant. No significant change was found for LTC4 and hyaluronic acid. Total concentrations of sodium naproxen were equivalent in plasma (16.1 micrograms.ml-1) and synovial fluid (18.9 micrograms.ml-1). Free fractions were significantly higher in synovial fluid (0.14%) than in plasma (0.11%), as shown by binding of the drug to human serum albumin, at various protein concentrations. Interestingly, the clinical efficacy, as shown by decreases in morning stiffness and in the Lee index score, correlated with the free concentration of naproxen in synovial fluid.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arthritis, Rheumatoid; Biomarkers; Chromatography, High Pressure Liquid; Dinoprostone; Female; Humans; Hyaluronic Acid; Immunoenzyme Techniques; Knee Joint; Leukotriene B4; Male; Middle Aged; Naproxen; Protein Binding; Synovial Fluid; Thromboxane B2

Alterations in renal eicosanoid levels have been postulated as a factor in cyclosporin A (CSA) nephrotoxicity. The effects of CSA on renal eicosanoid excretion in rheumatoid arthritis were studied over a 24-week period, during which treatment with nonsteroidal antiinflammatory drugs was discontinued. The initial dosage of CSA was 4 mg/kg/day; at week 24, the mean dosage of CSA was 3.9 mg/kg/day. At week 24, the mean (+/- SD) serum creatinine level (1.04 +/- 0.24 mg/dl) was 32% above the baseline value; renal blood flow had decreased by 21% (P less than 0.03) and the glomerular filtration rate had decreased by 16%. There was a significant increase (P less than 0.03) in the 2,3-dinor thromboxane B2 level at week 2, but there was no significant change in the levels of the other eicosanoids. This study demonstrates that after CSA treatment, there is a selective increase in a thromboxane metabolite that parallels an increase in renal vascular resistance, even in the absence of nonsteroidal antiinflammatory drugs, and with unimpaired formation of other vasodilator eicosanoids.

Topics: Adult; Aged; Arthritis, Rheumatoid; Creatinine; Cyclosporins; Eicosanoids; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Renal Circulation; Thromboxane B2

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Cells, Cultured; Eicosanoic Acids; Humans; Hydrocortisone; Leukotriene B4; Neutrophils; Penicillamine; Prostaglandins; Synovial Fluid; Thromboxane B2

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

Topics: 6-Ketoprostaglandin F1 alpha; Arthritis, Rheumatoid; Dinoprostone; Fatty Acids, Unsaturated; Humans; Prostaglandins E; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arthritis, Rheumatoid; Eicosanoic Acids; Humans; Middle Aged; Thromboxane B2

The effects of one-day treatment with nine nonsteroidal anti-inflammatory drugs and prednisolone on human synovial fluid concentrations of prostanoids were studied. The doses were calculated so as to be approximately equipotent according to clinical experience and the recommendations of the manufacturers. Most of the drugs used reduced clearly PGE2 and TxB2 levels in synovial fluid, but only a slight diminution in 6-keto-PGF1 alpha values was found. Carprofen, diclofenac, indomethacin, naproxen and tolfenamic acid reduced significantly the synovial fluid PGE2 concentrations. Diclofenac and indomethacin also reduced significantly the synovial TxB2 concentrations.

Topics: 6-Ketoprostaglandin F1 alpha; Acetaminophen; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Aspirin; Carbazoles; Diclofenac; Dinoprostone; Guanidines; Humans; Indomethacin; Naproxen; ortho-Aminobenzoates; Prednisolone; Prostaglandins; Prostaglandins E; Quinazolines; Synovial Fluid; Thromboxane B2

Topics: Arachidonic Acid; Arachidonic Acids; Arthritis, Rheumatoid; Diclofenac; Dinoprostone; Humans; Hydroxyeicosatetraenoic Acids; Metabolic Clearance Rate; Osteoarthritis; Prostaglandins E; Synovial Fluid; Thromboxane B2

In patients with rheumatoid arthritis high levels of prostaglandin E1 have been found in the joint fluid, and its increased production by adherent synovial cells and macrophages clearly supports the notion that this arachidonic acid metabolite is involved in the pathology of the disease. Besides its known inflammatory qualities and the suppressive effects on various lymphocyte functions prostaglandin E2 has proved to be an essential cofactor in the secretion of the lymphokine osteoclast activating factor. In this study we have discovered an enhanced release of prostaglandin E1 and thromboxane B2 from a subpopulation of blood monocytes from patients with rheumatoid arthritis and active systemic lupus erythematosus. No correlation between prostanoid release from monocytes and inflammatory activity of the disease was found. However, even monocytes from patients with early stage or mild inflammatory activity displayed a 'stimulated' arachidonic acid metabolism. In contrast only patients with active systemic lupus erythematosus showed in this respect comparable secretory activity or monocytes. Our findings may point to a possible pathogenic role of prostanoids in rheumatoid arthritis, which may also have some implication for the early diagnosis of this disease and for its differentiation from other chronic inflammatory rheumatic conditions.

Topics: Arthritis; Arthritis, Rheumatoid; Blood Sedimentation; Female; Humans; Lupus Erythematosus, Systemic; Lymphoproliferative Disorders; Male; Monocytes; Prostaglandins E; Thromboxane B2; Thromboxanes

The effect of l-histidine on arachidonic acid metabolism was studied in rabbit splenic fibroblast cultures and human platelets. The noradrenaline-stimulated generation of PGE2 in fibroblast cultures was inhibited by l-histidine dose dependently. In the same way l-histidine diminished the aggregation-induced synthesis of TXB2 in human platelets. In contrast to this, after incubation with l-histidine the generation of PGE2 in activated platelets increased in a dose dependent way up to 240% of pretreatment values. The further increase of l-histidine concentration resulted in an inhibition of platelet PGE2 synthesis. The present results demonstrate a differential influence of the amino acid l-histidine on cell arachidonic acid metabolism. It is concluded that the supposed anti-rheumatic property of l-histidine is caused by its effect on the synthesis of prostaglandins which are known to be mediators of inflammation.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Arthritis, Rheumatoid; Blood Platelets; Cells, Cultured; Dinoprostone; Histidine; Norepinephrine; Prostaglandins E; Rabbits; Spleen; Thromboxane B2

Production of various arachidonic acid metabolites from both endogenous and exogenous substrate was measured using cultures of synovial fibroblasts from healthy and rheumatic synovia. At first, the rheumatic cells showed retarded growth and an altered histological picture. Rheumatic cells produced more 6-keto-PGF1 alpha, the main metabolite of prostacyclin, and prostaglandin E2 than did normal cells, which synthesized more thromboxane B2. Later on these differences diminished or disappeared, except regarding 6-keto-PGF1 alpha. When fairly high concentrations of exogenous arachidonic acid were used, for 2-hour incubation of the cells, the production of identified metabolites, 6-keto-PGF1 alpha, PGF2 alpha, PGE2, PGD2, PGA + PGB and thromboxane B2, was slightly less in rheumatic cells. In general, the main metabolite formed was 6-keto-PGF1 alpha. Some kind of feedback mechanism between prostaglandins and cyclic nucleotides is suggested.

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acid; Arachidonic Acids; Arthritis, Rheumatoid; Dinoprostone; Epoprostenol; Fibroblasts; Humans; In Vitro Techniques; Prostaglandins E; Synovial Membrane; Thromboxane A2; Thromboxane B2

Specimens of human rheumatoid and nonrheumatoid synovial lining were maintained in nonproliferative organ culture for 20 hours. The culture fluids were then assayed for prostaglandin E(2) (PGE(2)), thromboxane B(2) (TXB(2)), and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)) by specific radioimmunoassay. The presence of each of these substances was confirmed by gas chromatography and mass spectrometry. Rheumatoid tissue produced significantly more of each cyclo-oxygenase product than nonrheumatoid tissue.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Arthritis, Rheumatoid; Dinoprostone; Female; Humans; Male; Middle Aged; Organ Culture Techniques; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Synovial Membrane; Thromboxane B2; Thromboxanes

No significant differences were found in plasma concentrations and urinary excretion of prostaglandin E2 (PGE2), 6-keto-prostaglandin-F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2), between rheumatoid arthritis patients and controls. However, urinary excretion of PGEe and 6-keto-PGF1 alpha tended to be greater and plasma levels of TxB2 lower in rheumatoid arthritis. Plasma concentrations and urinary excretion showed no marked circadian variation, although night or morning values were slightly lower. Plasma and urine prostaglandins do not correlate with clinical symptomatology in rheumatoid arthritis.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arthritis, Rheumatoid; Dinoprostone; Female; Humans; Male; Middle Aged; Prostaglandins E; Thromboxane B2; Thromboxanes

An original and easily reproducible technique for isolating and culturating mononucleated phagocytes from rheumatoid synovial fluid was used by the authors to study the synthesis of PGE2, PGF alpha 2 and TxB2 by macrophages taken from 16 patients with rheumatoid arthritis. The functional importance of these macrophages was evaluated by comparing their ratios of prostaglandin synthesis. PGE2 and TxB2 are released in large quantities and are increased after stimulation with zymosan. Two distinct cell populations having different biochemical characteristics were identified from these macrophages based on their capacity to synthesize prostaglandins. Prostaglandin synthesis was correlated with the clinical progression of rheumatoid arthritic disease as evaluated by Lee's index and the time required to loosen up morning joint stiffness in these patients. No correlation was found between prostaglandin synthesis and the quantity of synovial fluid in the affected joint. The first results of a pharmacological study evaluating the activity of non steroid anti-inflammatory drugs using this experimental model are presented here. The addition of indomethacin to culture medium produces dose-dependent inhibition of prostaglandin synthesis.

Topics: Adult; Aged; Arthritis, Rheumatoid; Female; Humans; Indomethacin; Macrophages; Male; Middle Aged; Prostaglandins; Synovial Fluid; Thromboxane B2; Thromboxanes

Topics: Arachidonic Acids; Arthritis, Rheumatoid; Cell Separation; Concanavalin A; Female; Humans; Lymphocyte Activation; Lymphocytes; Male; Monocytes; Prostaglandins; Prostaglandins E; Prostaglandins F; Thromboxane B2

1 The present study was undertaken to characterize the spectrum of arachidonic acid metabolites present in synovial effusions of patients with rheumatoid or psoriatic arthritis, and to compare changes in their concentration following a short-term treatment with 6alpha-methyl-prednisolone (6-MeP: 4-8 mg/day) or indoprofen (1.2 g/day), a nonsteroidal anti-inflammatory agent with proven synovial prostaglandin inhibitory effect.2 Measurements of prostaglandin E(2) (PGE(2)), thromboxane (TX) B(2), 6-keto-PGF(1alpha) and PGF(2alpha) were performed by radioimmunoassay techniques in synovial effusions obtained from 23 patients, and validated by thin-layer chromatographic analysis of the extracted immunoreactivity.3 PGE(2) and TXB(2) accounted for more than 60% of the total immunoreactivity in untreated patients. The absence of any constant ratio between the different arachidonic acid metabolites detected in synovial fluid is consistent with a heterogeneous cellular origin of these compounds.4 Indoprofen treatment was associated with a consistent reduction of synovial prostaglandin and thromboxane concentrations, ranging from 36% in the case of 6-keto-PGF(1alpha) to 90% in the case of PGE(2).5 In contrast, 6-MeP caused opposite changes on different metabolites originating via the cyclo-oxygenase pathway. Thus, 6-keto-PGF(1alpha) concentrations were reduced by 35%, PGF(2alpha) concentrations were increased by 30%, while PGE(2) and TXB(2) were unchanged following 6-MeP.6 Although the mechanism(s) underlying the failure of 6-MeP to reduce synovial PGE(2) and TXB(2) levels are uncertain, the results of the present study clearly indicate that therapeutic doses of steroidal and nonsteroidal anti-inflammatory drugs cause quite distinct changes in arachidonic acid metabolism, which might be relevant to their specific therapeutic actions and side-effects.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Arthritis, Juvenile; Arthritis, Rheumatoid; Female; Humans; Indoprofen; Male; Methylprednisolone; Middle Aged; Phenylpropionates; Prostaglandins; Prostaglandins E; Prostaglandins F; Synovial Fluid; Thromboxane B2; Thromboxanes

The present study was designed to characterize leukocytes of patients with rheumatoid arthritis (RA) with regard to proliferation of peripheral blood lymphocytes (PBL) and prostanoid release from circulating monocytes (M phi. Compared to cells of healthy individuals, PBL from RA patients exhibited a reduced mitogenic response to concanavalin A (Con A) which was associated with an increased capacity of circulating M phi to synthesize PGE and thromboxane B2 (TXB2). Addition of synovial fluid exudates of RA patients (RA-SFE) to peripheral blood leucocyte cultures produced three effects: A spontaneous proliferation of normal and RA-PBL, a reduction of the Con A response of normal and RA-PBL, a reduction of the Con A response of normal and RA-PBL, and an enhanced release of PGE and TXB2 from RA-M phi only. To elucidate the cellular origin of these activities, normal and RA-PBL were incubated with supernatants (SNT) os synovial cell cultures from RA patients and patients with non-RA joint diseases. SNT from Con A-stimulated synovial lymphocytes of both RA and control patients induced a spontaneous proliferation of normal and RA-PBL. In contrast, SNT from non-lymphoid adherent synovial cells of RA and control patients reduced the Con A response of normal and RA-PBL but a striking difference was noted in that an enhanced PGE and TXB2 release occurred only from M phi of RA patients.

Topics: Arthritis, Rheumatoid; Cell Division; Concanavalin A; Exudates and Transudates; Humans; In Vitro Techniques; Lymphocytes; Mitogens; Prostaglandins; Prostaglandins E; Synovial Fluid; Thromboxane B2; Thymidine

Topics: Aged; Arthritis, Rheumatoid; Epoprostenol; Female; Humans; Male; Middle Aged; Prostaglandins; Prostaglandins E; Prostaglandins F; Synovial Fluid; Thromboxane B2

Prostaglandins (PG) are currently suspected to be involved in human rheumatoid arthritis (RA). We have studied the PG [PGE2, PGF2 alpha, and Thromboxane B2 (TXB2)] biosynthesis capacity of normal (from amputations) and pathologic (osteoarthritis (OA) and RA) synovia. The measurement is done on the whole homogenate and microsomal fraction after 40 min incubation, without exogenous arachidonic acid (AA) or with a saturating concentration (25 micrograms/ml) of this compound, using a radioimmunoassay method. There is a considerable increase in PGE2 and PGF2 alpha production by the rheumatoid synovia and more PGE2 and PGF2 alpha are formed. This production is more marked for homogenates than microsomal fraction. The OA group is not homogeneous and does not differ significantly either from normals or from RA. The addition of AA considerably increases the biosynthesis of PG in both normal and pathologic tissue. For TXB2, the first results (four synovia) show no or a small biosynthesis in RA as well as in normals. Nevertheless, the levels before incubation seem higher in RA than in normal tissue.

Topics: Arachidonic Acids; Arthritis, Rheumatoid; Humans; Microsomes; Osteoarthritis; Prostaglandins E; Prostaglandins F; Synovial Membrane; Thromboxane B2; Thromboxanes

Prostaglandin F2 alpha (PGF2 alpha), prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) levels were determined by radioimmunoassay (RIA) in knee joint fluid in two groups of patients with classical or definite rheumatoid arthritis (RA). One group had no treatment for one week prior to the study. The second group consisted of patients who developed acute exudative arthritis despite the use of various non-steroidal anti-inflammatory drugs (NSAID). The main metabolites of PGF2 alpha in plasma and urine were measured in the untreated group. The conclusion to be drawn from this study are: 1) Treatment with NSAID effectively lowers PGF2 alpha and PGE2 and TXB2 levels in joint fluid. 2) Signs and symptoms of arthritis may persist in spite of lowered levels of PGF2 alpha and PGE2 in the joint fluid. 3) The main metabolites of PGF2 alpha in plasma and urine are above the low-normal limit in untreated patients. 4) The ratio TXB2/PG was low in untreated patients, suggesting that the thromboxane pathway is quantitatively minor in rheumatoid joint inflammation.

Topics: Anti-Inflammatory Agents; Arthritis, Rheumatoid; Female; Humans; Male; Prostaglandins E; Prostaglandins F; Synovial Fluid; Thromboxane B2; Thromboxanes