thromboxane-b2 and Arthritis

We investigated the occurrence of pharmacodynamic interaction between low-dose aspirin and naproxen.. The uncertainty of cardioprotection by naproxen has encouraged its combination with aspirin in patients with arthritis and cardiovascular disease.. The incubation of washed platelets with naproxen for 5 min before the addition of aspirin reduced the irreversible inhibition of thromboxane (TX)B(2) production by aspirin. The pharmacodynamic interaction between the two drugs was then investigated in four healthy volunteers who received aspirin (100 mg daily) for 6 days and then the combination of aspirin and naproxen for further 6 days: aspirin 2 h before naproxen (500 mg, twice-daily dosing). After 14 days of washout, naproxen was given 2 h before aspirin for further 6 days.. The inhibition of serum TXB(2) production (index of platelet cyclooxygenase [COX]-1 activity) and platelet aggregation ex vivo and urinary 11-dehydro-TXB(2) levels (index of TXB(2) biosynthesis in vivo) by aspirin alone (99 +/- 0.2%, 95 +/- 0.6%, and 81 +/- 4%, respectively) was not significantly altered by the co-administration of naproxen, given either 2 h after aspirin or in reverse order. In a second study, the concurrent administration of a single dose of aspirin and naproxen did not affect platelet TXB(2) production and aggregation at 1 h after dosing, when aspirin alone causes maximal inhibitory effect. Moreover, the rapid recovery of platelet COX-1 activity and function supports the occurrence of a pharmacodynamic interaction between naproxen and aspirin.. Naproxen interfered with the inhibitory effect of aspirin on platelet COX-1 activity and function. This pharmacodynamic interaction might undermine the sustained inhibition of platelet COX-1 that is necessary for aspirin's cardioprotective effects.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Aspirin; Cardiovascular Diseases; Cyclooxygenase 1; Drug Interactions; Drug Therapy, Combination; Humans; In Vitro Techniques; Membrane Proteins; Naproxen; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Thromboxane B2

Nonsteroidal antiinflammatory drugs (NSAID) are frequently reported to interfere with the blood pressure lowering actions of various antihypertensive medications. We studied 17 women with arthritis and hypertension who were receiving fosinopril and HCTZ, and administered sequentially in random order ibuprofen, sulindac, and nabumetone for 1 month each, with an intervening 2-week washout period between each treatment period. During the washout period, subjects received acetaminophen. Blood pressure at the end of 2 weeks of acetaminophen was compared with blood pressure after 1 month of treatment with each of the NSAID. Mean blood pressure was unchanged before and after all NSAID: 108 +/- 7 v 107 +/- 9 for nabumetone, 108 +/-9 v 108 +/- 9 for sulindac, and 108 +/- 8 v 107 +/- 9 for ibuprofen. The 24-h urinary sodium excretion was not significantly different. We conclude that the three NSAID did not neutralize the antihypertensive effect of the combination of fosinopril and HCTZ, and hence the blood pressure lowering action of the combination may not be prostaglandin dependent.

Topics: Acetaminophen; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Blood Pressure; Butanones; Creatinine; Dinoprostone; Diuretics; Drug Interactions; Drug Therapy, Combination; Female; Fosinopril; Glomerular Filtration Rate; Humans; Hydrochlorothiazide; Hypertension; Ibuprofen; Middle Aged; Nabumetone; Renal Plasma Flow; Sodium; Sodium Chloride Symporter Inhibitors; Sulindac; Thromboxane B2

Our aim was to determine the amounts of eicosanoids in blood and synovial tissue of patients with knee arthrosis and to examine the effects of 2 doses of tepoxalin (50 mg twice, 200 mg twice), administered p.o. for 3.5 days. Concentrations of leukotriene B4 (LTB4, LTC4, and thromboxane B2 (TXB2) were measured in blood before and after oral administration of tepoxalin and release of prostaglandin E2 (PGE2), 6-keto-PGF1alpha, and LTC4 was measured in incubation media of synovial tissue, taken at surgery from patients treated with tepoxalin. Radioimmunoassay (RIA) was used to determine the levels of the eicosanoids. LT and TXB2 release was reduced by tepoxalin in both doses used. Under these conditions, PGE2, 6-keto-PGF1alpha, and LTC4 release from synovial tissue was detectable only after stimulation with calcium ionophore A23187. Washed synovial tissue, in which tepoxalin concentrations should be reduced, released higher amounts of all eicosanoids measured than directly incubated synovial tissue did. Pain after tepoxalin administration was significantly reduced. Relevant drug concentrations were detected in plasma and synovial fluid. Tepoxalin was well tolerated and had no marked adverse effects. At 400 mg, tepoxalin is a dual inhibitor of cyclooxygenase (CO) and 5-lipoxygenase (5-LO) in blood and synovial tissue.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Arthroplasty, Replacement, Knee; Dinoprostone; Double-Blind Method; Drug Administration Schedule; Female; Humans; Knee Joint; Leukotriene Antagonists; Leukotriene B4; Leukotriene C4; Male; Middle Aged; Pain; Pain Measurement; Premedication; Pyrazoles; Radioimmunoassay; Synovial Membrane; Thromboxane B2

The effects of a 7 day-treatment with isoxicam (200 mg/24 h) on the urinary excretion of prostaglandins (PG) were compared to those of indomethacin (150 mg/24 h) in a double-blind randomized study conducted in 18 patients with degenerative arthritic disease and normal renal function. Indomethacin decreased the urinary excretion of PGF2 alpha by about 70% and 6-keto-PGF1 alpha and thromboxane (Tx)B2, the stable break-down products of prostacyclin and TxA2 respectively, by about 40%. Isoxicam effects on urinary PG did not significantly differ from those of indomethacin. During both treatments, urinary gamma-glutamyl transferase and N- acetyl-glucosaminidase remained stable and none of the changes in the urinary excretion of PGs could be related to either plasma or urinary drug concentrations. In conclusion, chronic administration of isoxicam inhibited the renal PG biosynthesis to a similar extent than indomethacin which suggests that non steroidal anti-inflammatory drugs of the oxicam group ought also be used cautiously in patients with renal impairment.

Topics: 6-Ketoprostaglandin F1 alpha; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Dinoprost; Double-Blind Method; Female; Humans; Indomethacin; Kidney Diseases; Male; Middle Aged; Piroxicam; Prostaglandins; Thromboxane B2

Amtolmetin guacyl (CAS 873344-06-7, MED 15) is a non-steroidal anti-inflammatory drug (NSAID) which has shown gastroprotective effects attributable to capsaicin receptor stimulation through the presence of a vanillic moiety in its molecular structure. The present paper further defines the anti-inflammatory activity of the product in an exudative rat model and in an arthritic rat model. The results obtained from both studies demonstrate anti-inflammatory effects comparable to those of the traditional NSAIDs in use. This study also demonstrated that amtolmetin guacyl possesses high antiaggregatory activity comparable to acetylsalicylic acid (CAS 50-78-2), when expressed as inhibition of blood thromboxane synthesis; the in vitro antiaggregatory activity was decidedly superior to that expressed by either acetylsalicylic acid or tolmetin (CAS 26171-23-3) (a traditional NSAID and metabolite of amtolmetin guacyl). The characteristics of gastroprotection along with control of inflammation and platelet aggregation render amtolmetin guacyl recommendable in the treatment of inflammatory and thromboembolic conditions where long-term therapy is required.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Arthritis; Body Weight; Bone Density; Carrageenan; Dose-Response Relationship, Drug; Exudates and Transudates; Glycine; In Vitro Techniques; Indomethacin; Male; Piroxicam; Platelet Aggregation; Platelet Aggregation Inhibitors; Pleurisy; Pyrroles; Rats; Thromboxane B2

The mechanism of action of FR140423 (3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)-phenyl]pyrazole), a novel and selective cyclooxygenase (COX)-2 inhibitor, in rat type II collagen-induced arthritis was investigated and compared with that of indomethacin. We tested the inhibitory effects of FR140423 on paw edema and the formation of arachidonic acid metabolites in inflamed paws immunized with type II collagen. Oral administration of FR 140423 showed a dose-dependent anti-inflammatory effect and was two-fold more potent than indomethacin. The increase of prostaglandin (PG) E2 and thromboxane (TX) B2 but not leukotriene B4 in inflamed paws was associated with the development of paw edema. FR140423 and indomethacin dose-dependently suppressed the levels of PGE2 and TXB2 in arthritic rat paws. Unlike indomethacin, FR140423 did not induce gastric lesions in arthritic rats. These results suggest that FR140423 shows a potent anti-inflammatory effect mediated by inhibition of prostanoids produced by COX-2 in inflamed tissues immunized with type II collagen, with a greatly improved safety profile compared to indomethacin.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Arthritis; Collagen; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Edema; Female; Gastric Mucosa; Indomethacin; Isoenzymes; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Inbred Lew; Sulfoxides; Thromboxane B2

The participation of lipid mediators and tumor necrosis factor (TNF) on an experimental model of immune-complex arthritis was investigated. Male Wistar rats received intraarticular injection of rabbit antibodies to bovine serum albumin into the knee joint followed by i.v. injection of the antigen. The levels of eicosanoids and TNF released into the synovial exudates were then assessed using ELISA and the L929 lytic cell assay, respectively. Increase in the levels of LTB4, TXB2 and PGE2 were detected 5 min, 5 min, and 6 h after arthritis induction, respectively. Pretreatment with the PAF receptor antagonist WEB 2170 decreased the levels of PGE2 and increased those of LTB4, without altering TXB2 levels. Increase in the levels of TNF was detected at 3 h of arthritis. Pretreatment with either the cycloxygenase inhibitor indomethacin or the 5-lipoxygenase inhibitor L-663,536 had no effect on TNF levels. Pretreatment with WEB 2170 significantly decreased TNF levels. These results are the first demonstration of eicosanoids and TNF release in immune-complex arthritis. The data also suggest that PAF had both a positive and negative modulatory role on the release of PGE2 and LTB4, respectively. Moreover, TNF release into the synovial exudate did not depend on eicosanoids whereas platelet activating factor (PAF) appeared to mediate the release of this cytokine in the model.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Arthus Reaction; Cattle; Dinoprostone; Eicosanoids; Indoles; Indomethacin; Injections, Intra-Articular; Leukotriene B4; Lipoxygenase Inhibitors; Male; Platelet Activating Factor; Rabbits; Rats; Rats, Wistar; Synovial Fluid; Thromboxane B2; Tumor Necrosis Factor-alpha

Colonisation with Helicobacter pylori may influence susceptibility to gastroduodenal injury and ulceration in patients taking non-steroidal anti-inflammatory drugs (NSAIDs). The aim of this study was to determine if Helicobacter pylori colonisation altered eicosanoid synthesis by gastric mucosa in these patients. Sixty five patients with long-standing NSAID intake and 23 control subjects underwent endoscopy. In vitro gastric antral biopsies were stimulated by vortex mixing and eicosanoid measurements determined by radioimmunoassay. Helicobacter pylori colonisation was determined by a CLO test (a gel based rapid urease test) and histological assessment. Median prostaglandin E2 synthesis by gastric mucosa was 61.0 (interquartile range: 19.2-73.1) pg/mg in control subjects colonised with Helicobacter pylori compared with 46.5 (23.3-65.5) pg/mg in Helicobacter pylori negative subjects. This was not significantly different. Treatment with NSAIDs was associated with a significant difference (p < 0.001) in prostaglandin E2 (PGE2) synthesis between those colonised with Helicobacter pylori (37.5(22.0-77.3) pg/mg) compared with patients not infected (12.6(7.0-19.3) pg/mg). Values in patients taking NSAIDs who were colonised were not different from control subjects. Synthesis of PGE2 was strongly associated with type B (chronic active), but not type C (chemical) gastritis. Dyspeptic symptoms were more common in subject colonised with Helicobacter pylori (p < 0.002) and were associated with higher PGE2 synthesis. In patients taking NSAIDs Helicobacter pylori colonisation removes rather then enhances depression of PGE2 synthesis associated with NSAIDs and may promote dyspepsia associated with ulcers and prevent superficial mucosal injury.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Dinoprostone; Female; Gastric Mucosa; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Smoking; Stomach Ulcer; 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

Peritoneal macrophages obtained from rats 21 days after induction of adjuvant arthritis and maintained in culture for 20 h in presence of [14C]-arachidonic acid and 10% foetal calf serum were found to have increased capacity for synthetizing prostacyclin and diminished capacity for synthetizing PGE2 compared with macrophages from normal rats. Similar results were obtained when foetal calf serum was replaced by either normal or arthritic rat serum. Orally administered indomethacin inhibited the increased synthesis of prostacyclin.

Topics: Animals; Arthritis; Arthritis, Experimental; Epoprostenol; Female; In Vitro Techniques; Macrophages; Prostaglandins; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains; Thromboxane B2

An acute inflammation was elicited in intertarsal joints of chicken by injection of urate crystals. Inflammatory exudates recovered at different times were assayed for prostaglandin D2(PGD2)E2 and F2 alpha and thromboxane B2 content by specific radioimmunoassays. We found that PGD2 was the prevailing prostaglandin reaching concentrations up to 10 times in excess of PGE2. This finding was confirmed by gas chromatography-mass spectrometry. It is concluded that PGD2 should be considered as a possible mediator of acute inflammation.

Topics: Animals; Arthritis; Chickens; Exudates and Transudates; Humans; Prostaglandins; Prostaglandins D; Prostaglandins E; Prostaglandins F; Thromboxane B2; Time Factors; Uric Acid