thromboxane-b2 and Osteoarthritis

We performed a placebo-controlled, randomized study to address whether celecoxib or ibuprofen undermines the functional range of inhibition of platelet cyclooxygenase (COX)-1 activity by aspirin in patients with osteoarthritis and stable ischemic heart disease.. Twenty-four patients who were undergoing long-term treatment with aspirin (100 mg daily) for cardioprotection were coadministered celecoxib, 200 mg twice daily, ibuprofen, 600 mg 3 times daily, or placebo for 7 days.. The coadministration of placebo or celecoxib did not undermine the aspirin-related inhibition of platelet COX-1 activity, as assessed by measurements of serum thromboxane B(2) (TXB(2)) levels, as well as platelet function. In contrast, a significant (P < .001) increase in serum TXB(2) level was detected on day 7 before drug administration (median, 19.13 ng/mL [range, 1-47.5 ng/mL]) and at 24 hours after the coadministration of aspirin and ibuprofen (median, 22.28 ng/mL [range, 4.9-44.4 ng/mL]) versus baseline (median, 1.65 ng/mL [range, 0.55-79.8 ng/mL]); this was associated with a significant increase in arachidonic acid-induced platelet aggregation (P < .01) and adenosine diphosphate-induced platelet aggregation (P < .05) and a decrease in the time to form an occlusive thrombus in the platelet function analyzer (P < .01). The urinary excretion of 11-dehydro-TXB(2), an index of systemic thromboxane biosynthesis, was not significantly affected by the coadministration of treatment drugs. At steady state, a comparable and persistent inhibition of lipopolysaccharide-stimulated prostaglandin E(2) generation, a marker of COX-2 activity ex vivo, was caused by ibuprofen (>or=80%) or celecoxib (>or=70%) but not placebo.. Unlike ibuprofen, celecoxib did not interfere with the inhibition of platelet COX-1 activity and function by aspirin despite a comparable suppression of COX-2 ex vivo in patients with osteoarthritis and stable ischemic heart disease.

Topics: Adenosine Diphosphate; Aged; Arachidonic Acid; Aspirin; Celecoxib; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Ibuprofen; Male; Middle Aged; Myocardial Ischemia; Osteoarthritis; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Pyrazoles; Sulfonamides; Thromboxane B2; Treatment Outcome

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

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

The role of PGD2 has been recognized in allergy, innate immunity and inflammation. Western blot analysis identified 21 kDa lipocalin (L)-prostaglandin D2 (PGD2) synthase (S) in human osteoarthritis (OA)-affected cartilage, whose expression was increased by IL-1β and TNFα. Similarly, PGD2 was spontaneously released by human OA-affected cartilage (and upregulated by IL-β) in ex vivo conditions and could be inhibited by indomethacin. Addition of PGD2 to human OA-affected cartilage significantly increased accumulation of PGE2, PGF1α, PGF2α, TXB2, but inhibited LTB4 and nitric oxide (NO) accumulation. Similarly, PGD2 (but not 13,14-dihydro-15-keto PGD2) augmented IL-1β induced PGE2 but inhibited IL-β induced nitric oxide (NO) in human chondrocytes. Celecoxib (10 μM) inhibits COX-1 mediated PGD2, and nitric oxide synthase (NOS) mediated NO in human OA-affected cartilage. Furthermore, celecoxib (1 μM) counter balances (IL-1β induced+PGD2 modulated) levels of NO and PGE2 in human OA-affected cartilage and chondrocytes to basal levels. These results show concentration-dependent, pro- and anti-inflammatory activity of PGD2 in human chondrocytes and cartilage, which can be neutralized by celecoxib. In view of the broad prostaglandin dependent and independent mechanism of action of celecoxib, these observations further reaffirm the broader role of celecoxib as a "Disease Modifying Drug" for human Osteoarthritis.

Topics: Celecoxib; Cells, Cultured; Chondrocytes; Dinoprost; Dinoprostone; Humans; Inflammation Mediators; Interleukin-1beta; Knee; Leukotriene B4; Nitric Oxide; Osteoarthritis; Prostaglandin D2; Prostaglandins F; Pyrazoles; Sulfonamides; Thromboxane B2

Prostaglandin E synthase (PGES) including isoenzymes of membrane-associated PGES (mPGES)-1, mPGES-2, and cytosolic PGES (cPGES) is the recently identified terminal enzyme of the arachidonic acid cascade. PGES converts prostaglandin (PG)H2 to PGE2 downstream of cyclooxygenase (COX). We investigated the expression of PGES isoenzyme in articular chondrocytes from patients with osteoarthritis (OA). Chondrocytes were treated with various cytokines and the expression of PGES isoenzyme mRNA was analyzed by the reverse transcription-polymerase chain reaction and Northern blotting, whereas Western blotting was performed for protein expression. The subcellular localization of mPGES-1 was determined by immunofluorescent microscopy. Conversion of arachidonic acid or PGH2 to PGE2 was measured by enzyme-linked immunosorbent assay. Finally, the expression of mPGES-1 protein in OA articular cartilage was assessed by immunohistochemistry. Expression of mPGES-1 mRNA in chondrocytes was significantly induced by interleukin (IL)-1beta or tumor necrosis factor (TNF)-alpha, whereas other cytokines, such as IL-4, IL-6, IL-8, IL-10, and interferon-gamma, had no effect. COX-2 was also induced under the same conditions, although its pattern of expression was different. Expression of cPGES, mPGES-2, and COX-1 mRNA was not affected by IL-1beta or TNF-alpha. The subcellular localization of mPGES-1 and COX-2 almost overlapped in the perinuclear region. In comparison with 6-keto-PGF1alpha and thromboxane B2, the production of PGE2 was greater after chondrocytes were stimulated by IL-1beta or TNF-alpha. Conversion of PGH2 to PGE2 (PGES activity) was significantly increased in the lysate from IL-1beta-stimulated chondrocytes and it was inhibited by MK-886, which has an inhibitory effect on mPGES-1 activity. Chondrocytes in articular cartilage from patients with OA showed positive immunostaining for mPGES-1. These results suggest that mPGES-1 might be important in the pathogenesis of OA. It might also be a potential new target for therapeutic strategies that specifically modulate PGE2 synthesis in patients with OA.

Topics: 6-Ketoprostaglandin F1 alpha; Cartilage, Articular; Cells, Cultured; Chondrocytes; Cyclooxygenase 2; Cytokines; Humans; Indoles; Inflammation; Interleukin-1; Intramolecular Oxidoreductases; Isoenzymes; Membrane Proteins; Osteoarthritis; Phenotype; Prostaglandin-E Synthases; Prostaglandin-Endoperoxide Synthases; RNA, Messenger; Thromboxane B2; Time Factors; Up-Regulation

To evaluate in vivo activity in dogs of meloxicam or aspirin, previously shown in vitro to be a selective cyclooxygenase-2 (COX-2) inhibitor (COX-1 sparing drug), or a nonselective COX inhibitor, respectively.. 12 male dogs with unilateral osteoarthritis of the stifle joint.. Each dog was treated in a crossover design with aspirin or meloxicam for 21 days. Prostaglandin E2 (PGE2) concentrations were measured at days 0 (baseline), 7, and 21 of each treatment period in lipopolysaccharide (LPS)-stimulated blood, synovial fluid collected by arthrocentesis, and endoscopic gastric mucosal biopsy specimens. Thromboxane B2 (TXB2) was evaluated in blood on days 0, 7, and 21 of each treatment period.. Aspirin administration significantly suppressed PGE2 concentrations in blood, gastric mucosa, synovial fluid, and suppressed TXB2 concentration in blood at days 7 and 21. Meloxicam administration significantly suppressed PGE2 concentrations in blood and synovial fluid at days 7 and 21, but had no effect on concentrations of TXB2 in blood or PGE2 in gastric mucosa. Suppression of LPS-stimulated PGE2 concentrations in blood and synovial fluid by aspirin and meloxicam administration is consistent with activity against the COX-2 isoenzyme. Suppression of concentrations of PGE2 in the gastric mucosa and TXB2 in blood by aspirin administration is consistent with activity against COX-1. Meloxicam, in contrast, had a minimal effect on functions mediated by COX-1.. Meloxicam acts in vivo in dogs as a COX-1 sparing drug on target tissues by sparing gastric PGE2 synthesis while retaining antiprostaglandin effects within inflamed joints.

Topics: Animals; Aspirin; Cross-Over Studies; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Dinoprostone; Dog Diseases; Dogs; Gastric Mucosa; Isoenzymes; Male; Meloxicam; Osteoarthritis; Prostaglandin-Endoperoxide Synthases; Stifle; Synovial Fluid; Thiazines; Thiazoles; Thromboxane B2

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