thromboxane-b2 and rofecoxib

To investigate the rate of platelet thromboxane (TX) biosynthesis and its determinants in Alzheimer's disease.. A cross-sectional comparison of urinary 11-dehydro-TXB(2) and 8-iso-prostaglandin (PG)F(2alpha) (markers of in vivo platelet activation and lipid peroxidation, respectively), plasma Vitamin E, C-reactive protein (CRP), tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, was carried-out in 44 Alzheimer patients and 44 matched controls. To investigate the cyclooxygenase (COX)-isoform involved in TXA(2) biosynthesis, nine Alzheimer patients were treated with low-dose aspirin (100mg/d) or rofecoxib (25mg/d) for 4 days. Urinary 11-dehydro-TXB(2) and 8-iso-PGF(2alpha) were significantly higher in Alzheimer patients than in controls (Median: 1983.5 versus 517.5pg/mg creatinine and 938.5 versus 304.0pg/mg creatinine, p<0.0001, respectively), with a significant correlation between the two metabolites (rho=0.75, p<0.0001). An inverse correlation was observed between Vitamin E and both urinary metabolites (8-iso-PGF(2alpha): R(s)=-0.51, p=0.0004; 11-dehydro-TXB(2): R(s)=-0.44, p=0.0026) in Alzheimer patients. No difference was found in CRP, TNF-alpha and IL-6 levels between the two groups. Urinary 11-dehydro-TXB(2) was significantly reduced by aspirin, but not by rofecoxib, consistently with a COX-1-mediated TXA(2) biosynthesis. 8-iso-PGF(2alpha) excretion was not modified by either COX-inhibitor, consistently with its oxygen radical-catalyzed formation.. Platelet activation is persistently enhanced in Alzheimer's disease. This is related, at least in part, to increased lipid peroxidation associated with inadequate levels of Vitamin E.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Aspirin; Body Mass Index; C-Reactive Protein; Case-Control Studies; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Cyclooxygenase 2 Inhibitors; Dinoprost; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-6; Lactones; Logistic Models; Male; Odds Ratio; Platelet Activation; Radioimmunoassay; Sulfones; Thromboxane B2; Tumor Necrosis Factor-alpha; Vitamin E

To test the hypothesis that selective inhibition of cyclooxygenase (COX)-2 would result in exercise-induced platelet activation by causing a shift in the endogenous thromboxane (TX)/prostacyclin balance, a double blind, randomized study comparing aspirin (300 mg/d) with rofecoxib (25 mg/d) (cross-over design, 14 days washout between treatments) in n = 10 trained healthy volunteers was carried out. Physical exercise resulted only in a minor platelet activation, as reflected by the expression of basal or ADP-stimulated platelet activation markers or basal plasma concentrations of TXB(2). Aspirin significantly reduced TXB(2) in plasma while rofecoxib significantly increased TXB(2) in urine. Although no increase in systemic prostacyclin concentration was observed, there was a significant exercise-related increase in both platelet cAMP and cGMP without any drug-related effects. It is concluded that, in trained healthy volunteers, selective inhibition of COX-1 (aspirin) or COX-2 (rofecoxib) does not affect systemic prostacyclin synthesis after physical exercise. However, our data do not exclude the possibility that in subjects at risk for atherothrombotic complications (e.g. patients with advanced atherosclerotic disease) COX-2 inhibitors may result in platelet activation by inhibiting endothelial prostacyclin formation.

Topics: Adenosine Diphosphate; Adult; Aspirin; Atherosclerosis; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Double-Blind Method; Endothelium; Epoprostenol; Exercise; Humans; Isoenzymes; Lactones; Male; Platelet Activation; Rest; Risk Factors; Sulfones; Thrombosis; Thromboxane B2

Leukotriene (LT) B4 concentrations are increased and prostaglandin (PG) E2 concentrations are decreased in exhaled breath condensate (EBC) in patients with chronic obstructive pulmonary disease (COPD). A study was undertaken to investigate the short term effects of cyclo-oxygenase (COX) inhibition on exhaled LTB4 and PGE2 concentrations in patients with COPD and to identify the COX isoform responsible for exhaled PGE2 production.. Two studies were performed. A double blind, crossover, randomised, placebo controlled study with ibuprofen (400 mg qid for 2 days), a non-selective COX inhibitor, was undertaken in 14 patients with stable COPD, and an open label study with oral rofecoxib (25 mg once a day for 5 days), a selective COX-2 inhibitor, was undertaken in a different group of 16 COPD patients. EBC was collected before and after drug treatment. Exhaled LTB4 and PGE2 concentrations were measured with specific immunoassays.. All patients complied with treatment as indicated by a reduction in ex vivo serum thromboxane B2 concentrations (ibuprofen) and a reduction in lipopolysaccharide induced increase in ex vivo plasma PGE2 values (rofecoxib) of more than 80%. Exhaled LTB4 was increased after ibuprofen (median 175.5 (interquartile range 128.8-231.5) pg/ml v 84.0 (70.0-98.5) pg/ml, p < 0.001) and exhaled PGE2 was reduced (93.5 (84.0-105-5) pg/ml v 22.0 (15.0-25.5) pg/ml, p < 0.0001). Rofecoxib had no effect on exhaled LTB4 (p = 0.53) or PGE2 (p = 0.23).. Non-selective COX inhibition decreases PGE2 and increases LTB4 in EBC, whereas selective COX-2 inhibition has no effect on these eicosanoids. PGE2 in EBC is primarily derived from COX-1 activity, and COX inhibition may redirect arachidonic acid metabolism towards the 5-lipoxygenase pathway.

Topics: Blood Gas Analysis; Cross-Over Studies; Cyclooxygenase Inhibitors; Dinoprostone; Double-Blind Method; Eicosanoids; Female; Forced Expiratory Volume; Humans; Ibuprofen; Lactones; Leukotriene B4; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Sputum; Sulfones; Thromboxane B2; Vital Capacity

Balance between vasoactive prostanoids that contribute to homeostasis of the circulatory system can be affected by cyclooxygenases inhibitors. Results of a recent large clinical trial show that myocardial infarction was more frequent among patients with rheumatoid arthritis treated with the selective cyclooxygenase-2 inhibitor rofecoxib compared with those treated with naproxen. Whether this difference was attributable to deleterious cardiovascular effects of rofecoxib or cardioprotective effects of naproxen has not been determined. We tested the hypothesis that naproxen, contrary to rofecoxib, exerts antithrombotic effects.. Forty-five healthy men were randomized to receive a 7-day treatment with rofecoxib (50 mg/d), naproxen (1000 mg/d), aspirin (75 mg/d), or diclofenac (150 mg/d). Formation of thromboxane, prostacyclin, and thrombin in the bleeding-time blood at the site of standardized microvascular injury was assessed before and after treatment. Naproxen, like aspirin, caused significant reduction of both thromboxane and prostacyclin, whereas diclofenac depressed prostacyclin synthesis but had no effect on tromboxane formation. Naproxen and aspirin significantly suppressed thrombin generation. Diclofenac showed a similar tendency, which did not reach statistical significance. Rofecoxib had no effect on any variables measured.. In healthy men, naproxen exerts an antithrombotic effect at least as potent as aspirin, whereas rofecoxib does not affect hemostatic balance.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Bleeding Time; Blood Platelets; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Diclofenac; Double-Blind Method; Endothelium, Vascular; Fibrinolytic Agents; Humans; Isoenzymes; Lactones; Male; Membrane Proteins; Naproxen; Prostaglandin-Endoperoxide Synthases; Sulfones; Thrombin; Thromboxane B2

Rofecoxib, an inhibitor of the inducible cyclooxygenase (COX)-2 enzyme, appears not to cause acute gastroduodenal injury or chronic ulceration. To attribute this to COX-2 selectivity with sparing of gastric mucosal prostaglandin synthesis requires direct proof.. Twenty-four healthy, nonsmoking Helicobacter pylori-negative volunteers were randomized to 1 of 2 separate concurrent blinded crossover studies. Sixteen volunteers received rofecoxib, 50 mg once daily, for 5 days in one treatment period and placebo in the other. Eight volunteers similarly received naproxen, 500 mg twice daily, and placebo. On day 5 of each period, antral mucosal prostaglandin E2 (PGE2) synthesis was measured by radioimmunoassay after vortexing for 3 minutes. Whole blood COX-1 activity was measured as serum thromboxane (TXB)2- and COX-2 activity as lipopolysaccharide (LPS)-induced PGE2.. Naproxen decreased gastric mucosal PGE2 synthesis by 65% (90% confidence interval [CI], 53%-74%; P = 0.001 vs. placebo) in contrast to an 18% increase after rofecoxib (90% CI, -11% to 57%; P = 0.313 vs. placebo). Naproxen also significantly inhibited both serum TXB2 by 94% and LPS-induced PGE2 production by 77% (both P < or = 0.002 vs. placebo), but rofecoxib only inhibited COX-2-dependent LPS-induced PGE(2) (by 79%; P < 0.001 vs. placebo).. Rofecoxib (50 mg) lacked naproxen's ability to reduce the availability of gastroprotective prostaglandins.

Topics: Adult; Cross-Over Studies; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Double-Blind Method; Female; Gastric Mucosa; Humans; Isoenzymes; Lactones; Lipopolysaccharides; Male; Membrane Proteins; Naproxen; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Sulfones; Thromboxane B2

Patients with arthritis and vascular disease may receive both low-dose aspirin and other nonsteroidal antiinflammatory drugs. We therefore investigated potential interactions between aspirin and commonly prescribed arthritis therapies. We administered the following combinations of drugs for six days: aspirin (81 mg every morning) two hours before ibuprofen (400 mg every morning) and the same medications in the reverse order; aspirin two hours before acetaminophen (1000 mg every morning) and the same medications in the reverse order; aspirin two hours before the cyclooxygenase-2 inhibitor rofecoxib (25 mg every morning) and the same medications in the reverse order; enteric-coated aspirin two hours before ibuprofen (400 mg three times a day); and enteric-coated aspirin two hours before delayed-release diclofenac (75 mg twice daily). Serum thromboxane B(2) levels (an index of cyclooxygenase-1 activity in platelets) and platelet aggregation were maximally inhibited 24 hours after the administration of aspirin on day 6 in the subjects who took aspirin before a single daily dose of any other drug, as well as in those who took rofecoxib or acetaminophen before taking aspirin. In contrast, inhibition of serum thromboxane B(2) formation and platelet aggregation by aspirin was blocked when a single daily dose of ibuprofen was given before aspirin, as well as when multiple daily doses of ibuprofen were given. The concomitant administration of rofecoxib, acetaminophen, or diclofenac did not affect the pharmacodynamics of aspirin. The concomitant administration of ibuprofen but not rofecoxib, acetaminophen, or diclofenac antagonizes the irreversible platelet inhibition induced by aspirin. Treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin.

Topics: Acetaminophen; Adult; Analgesics, Non-Narcotic; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cross-Over Studies; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Diclofenac; Dinoprostone; Drug Interactions; Drug Therapy, Combination; Humans; Ibuprofen; Isoenzymes; Lactones; Membrane Proteins; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandin-Endoperoxide Synthases; Sulfones; Thromboxane B2

Prostaglandin synthesis is catalyzed by a constitutive cyclo-oxygenase isoform (COX-1) and an inducible isoform (COX-2). It is hypothesized that the analgesic and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (nonspecific COX-1/COX-2 inhibitors) such as ibuprofen principally derive from COX-2 inhibition. The purpose of this study was to evaluate steady-state pharmacokinetics, biochemical selectivity and tolerability of rofecoxib (Vioxx), characterized in vitro as a COX-2 inhibitor.. Four panels of healthy men (n = 8 per panel) were administered rofecoxib (n = 6) (25, 100, 250, 375 mg) or placebo (n = 2) once daily on day 1 and days 3-14. Blood samples for assays of rofecoxib plasma concentration and COX isoform activity were obtained pre-dose and at specified time points post-dose.. Rofecoxib pharmacokinetics were found to be complex and nonlinear. Elimination half-life ranged from 9.9 h to 17.5 h after multiple dosing with an accumulation ratio close to 2 for all doses. COX-2 inhibitory activity as assessed by average inhibition of whole blood lipopolysaccharide-stimulated prostaglandin E2 over the 8-h post-dose period on day 14 was 0.3, 67, 96, 92 and 96% for the placebo and the 25-, 100-, 250- and 375-mg treatment groups, respectively. No treatment group showed significant inhibition of COX-1 as assessed by thromboxane B2 generation in clotting whole blood. Side effects were mild and transient.. The results indicate that rofecoxib is a potent and specific inhibitor of COX-2 in humans even at doses more than tenfold higher than those associated with efficacy in patients with osteoarthritis.

Topics: Adult; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Double-Blind Method; Enzyme Inhibitors; Humans; Isoenzymes; Lactones; Male; Membrane Proteins; Metabolic Clearance Rate; Placebos; Prostaglandin-Endoperoxide Synthases; Sulfones; Thromboxane B2

Steady-state inhibitory activity of rofecoxib (Vioxx) on COX-2 versus COX-1 was compared with that of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) in 76 healthy volunteers randomized to placebo, rofecoxib 12.5 mg qd, rofecoxib 25 mg qd, diclofenac 50 mg tid, ibuprofen 800 mg tid, sodium naproxen 550 mg bid, or meloxicam 15 mg qd. All of these doses include the high end of the approved clinical dose range. Ex vivo whole-blood assays were used to determine the effect on COX-2 and COX-1 activity, respectively. Urinary prostanoids were also measured. Mean inhibition of COX-2 (measured as the weighted average inhibition [WAI] of lipopolysaccharide [LPS]-induced PGE2 generation over 8 hours on day 6 vs. baseline) was -2.4%, 66.7%, 69.2%, 77.5%, 93.9%, 71.4%, and 71.5% for placebo, rofecoxib 12.5 mg, rofecoxib 25 mg, meloxicam, diclofenac, ibuprofen, and naproxen, respectively. Corresponding values for mean inhibition of COX-1 (measured as TXB2 generation in clotting whole blood) were -5.15%, 7.98%, 6.65%, 53.3%, 49.5%, 88.7%, and 94.9%. Rofecoxib had no significant effect on urinary excretion of 11-dehydro TXB2, a COX-1-derived product. These data support the contention that rofecoxib is the only drug of the regimens tested that uniquely inhibits COX-2 without affecting COX-1.

Topics: Adolescent; Adult; Bleeding Time; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Diclofenac; Dinoprostone; Female; Humans; Ibuprofen; Isoenzymes; Lactones; Lipopolysaccharides; Meloxicam; Membrane Proteins; Middle Aged; Naproxen; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Sulfones; Thiazines; Thiazoles; Thromboxane B2

The present study examined whether rofecoxib (VIOXX), a new specific inhibitor of cyclooxygenase-2 (COX-2), would interfere with the desired antiplatelet effects of aspirin. Thus, the effects of rofecoxib on inhibition of ex vivo serum-generated thromboxane B2 (TXB2) and platelet aggregation by low doses (81 mg) of aspirin were examined in healthy volunteers. This was a double-blind, randomized, placebo-controlled, parallel study of two treatment groups (n = 12 per group) in which subjects received 50 mg of rofecoxib or placebo for 10 days in a blinded fashion. Subjects also received 81 mg aspirin once on each of days 4 through 10 in an open-label fashion. Blood for measurement of serum TXB2 production and platelet aggregation studies was collected on day 1 (prior to rofecoxib/placebo), on day 4 (prior to aspirin), and on day 10 (before and 4 hours following the seventh dose of aspirin). Platelet-derived serum TXB2 (COX-1 assay) was measured in blood clotted for 1 hour at 37 degrees C. Platelet aggregation was independently induced employing 1 mM arachidonic acid and 1 microgram/mL collagen as agonists. Rofecoxib administered alone had no significant effect on serum TXB2 production or platelet aggregation (day 4). TXB2 production was inhibited 98.4% by aspirin coadministered with either rofecoxib or placebo (day 10). Similarly, platelet aggregation induced by arachidonic acid was inhibited 93.7% and 93.5% by aspirin coadministered with either rofecoxib or placebo, respectively (day 10). The comparable values for inhibition of collagen-induced platelet aggregation were 86.8% and 90.8%, respectively. No important clinical or laboratory adverse experiences were observed. In conclusion, rofecoxib alone (50 mg QD for 4 days) did not inhibit serum TXB2 production or platelet aggregation. In addition, rofecoxib (50 mg QD for 10 days) did not alter the antiplatelet effects of low-dose aspirin (inhibition of platelet aggregation and TXB2 production). Rofecoxib was generally well tolerated when administered alone or in combination with low-dose aspirin.

Topics: Adolescent; Adult; Aspirin; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Double-Blind Method; Drug Interactions; Female; Humans; Isoenzymes; Lactones; Male; Membrane Proteins; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandin-Endoperoxide Synthases; Sulfones; Thromboxane B2

Conventional nonsteroidal anti-inflammatory drugs inhibit both cyclooxygenase (Cox) isoforms (Cox-1 and Cox-2) and may be associated with nephrotoxicity. The present study was undertaken to assess the renal effects of the specific Cox-2 inhibitor, MK-966. Healthy older adults (n = 36) were admitted to a clinical research unit, placed on a fixed sodium intake, and randomized under double-blind conditions to receive the specific Cox-2 inhibitor, MK-966 (50 mg every day), a nonspecific Cox-1/Cox-2 inhibitor, indomethacin (50 mg t.i.d.), or placebo for 2 weeks. All treatments were well tolerated. Both active regimens were associated with a transient but significant decline in urinary sodium excretion during the first 72 h of treatment. Blood pressure and body weight did not change significantly in any group. The glomerular filtration rate (GFR) was decreased by indomethacin but was not changed significantly by MK-966 treatment. Thromboxane biosynthesis by platelets was inhibited by indomethacin only. The urinary excretion of the prostacyclin metabolite 2,3-dinor-6-keto prostaglandin F1alpha was decreased by both MK-966 and indomethacin and was unchanged by placebo. Cox-2 may play a role in the systemic biosynthesis of prostacyclin in healthy humans. Selective inhibition of Cox-2 by MK-966 caused a clinically insignificant and transient retention of sodium, but no depression of GFR. Inhibition of both Cox isoforms by indomethacin caused transient sodium retention and a decline in GFR. Our data suggest that acute sodium retention by nonsteroidal anti-inflammatory drugs in healthy elderly subjects is mediated by the inhibition of Cox-2, whereas depression of GFR is due to inhibition of Cox-1.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Aged, 80 and over; Blood Platelets; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Double-Blind Method; Eicosanoids; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Indomethacin; Isoenzymes; Lactones; Male; Membrane Proteins; Middle Aged; Prostaglandin-Endoperoxide Synthases; Sodium; Sulfones; Thromboxane B2; Water-Electrolyte Balance

Post-surgical pericardial adhesions pose an increased risk of complications during redo sternotomies. Adhesive tissue formation is a normal response to tissue injury and involves complex patho-physiological processes including the actions of prostaglandins to cause plasma leakage and fibrin formation. The purpose of this study was to assess the ability of two non-steroidal anti-inflammatory agents (Indomethacin and Rofecoxib) and a barrier (Coseal, a polyethylene glycol) to limit adhesion formation following cardiac surgery in a pig model.. Forty-four piglets were allocated equally to four treatment groups: Group 1: Control, Group 2: intramuscular Indomethacin, Group 3: oral Rofecoxib and Group 4: Coseal sprayed on the heart. A full median sternotomy was performed on each animal and the heart exposed. Adhesions were induced by rubbing tissues with gauze, applying sutures and leaving blood in the pericardial sac before chest closure. Plasma inflammatory markers including prostaglandin E(2) and thromboxane B(2) were measured preoperatively and on Days 2, 5 and 10 after surgery. Eight animals from each group were slaughtered after 12 weeks and 3 after 25 weeks. Adhesions were assessed macroscopically and microscopically.. Compared to the Control group, the extent of adhesions was significantly less in all other groups whilst adhesion density was least in the Indomethacin and Coseal groups. Indomethacin and less so Rofecoxib, inhibited the synthesis of prostaglandin E(2) and thromboxane B(2) but there were no significant changes in other inflammatory markers.. We conclude that systemic Indomethacin, and locally applied Coseal are suitable methods to markedly reduce pericardial and retrosternal adhesions.

Topics: Animals; Biological Availability; Biomarkers; Cyclooxygenase 2 Inhibitors; Dinoprostone; Disease Models, Animal; Drug Monitoring; Indomethacin; Inflammation; Lactones; Pericardium; Perioperative Period; Polyethylene Glycols; Postoperative Complications; Sternotomy; Sulfones; Surface-Active Agents; Swine; Thromboxane B2; Tissue Adhesions; Treatment Outcome

Upregulation of cyclooxygenase-2 (COX-2), an inducible enzyme that is actively involved in inflammation and wound healing, has been found in cirrhotic livers. The aim of this study was to investigate the effects of selective inhibition of COX-2 on the development of liver cirrhosis and portal hypertension in rats.. Liver cirrhosis was induced by carbon tetrachloride (CCl(4)) in Sprague-Dawley rats. Rofecoxib, a highly selective COX-2 inhibitor, was orally administered to rats at a dose of 10 mg/kg/day. Portal pressure was measured at 8 weeks post CCl(4) administration with the catheterization method followed by the harvesting of liver samples. Liver histopathology was analyzed with hematoxylin and eosin and Masson's trichrome staining. The activated, alpha smooth muscle actin (alpha-SMA) positive hepatic stellate cells (HSCs) and the protein levels of collagen types I, III, IV, as well as laminin and two fibrogenic mediators, vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) in the livers, were detected with immunohistochemical staining and western blot methods, respectively. The level of hepatic thromboxane B(2) (TXB(2)), a potent vasoconstrictive substance derived from COX, was measured with enzyme immunoassay.. Oral administration of rofecoxib decreased portal pressure in rats that were treated with CCl(4) for 8 weeks. This was associated with a marked reduction in collagen accumulation and TXB(2) level in the rat livers. In addition, rofecoxib administration was found to reduce the number of activated HSCs and to downregulate hepatic protein levels of three detected types of collagen, laminin, VEGF and CTGF in CCl(4)-treated rats.. COX-2 is involved in the fibrogenesis of livers and the formation of portal hypertension in CCl(4)-treated rats. Selective inhibition of COX-2 by rofecoxib reduces portal hypertension and this is associated with antifibrotic activity as well as a reduction of COX-2-derived vasoactive substance.

Topics: Administration, Oral; Analysis of Variance; Animals; Blotting, Western; Carbon Tetrachloride Poisoning; Collagen; Connective Tissue Growth Factor; Cyclooxygenase 2 Inhibitors; Hypertension, Portal; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Lactones; Laminin; Liver Cirrhosis, Experimental; Male; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric; Sulfones; Thromboxane B2; Vascular Endothelial Growth Factor A

This study evaluates the action of celecoxib and rofecoxib, two selective cyclooxygenase-2 (COX-2) inhibitors in two acute models of inflammation, carrageenan (Cg)-induced rat pleurisy, and paw oedema formation.. Male Wistar rats (N = 4-10 per group) were used. A fixed volume of PBS or carrageenan was injected into the pleural cavity or into the paw. Furthermore, the myeloperoxidase (MPO) activity and the levels of nitrite/nitrate (NOx), interleukin-1beta (IL-1beta), tumor necrosis factor-a (TNF-a) and PGE2 were also assessed in the paw tissue or in pleural exudate.. Dexamethasone (DEX, 0.5 mg kg(-1), s.c., -4 h) and indomethacin (INDO, 3 mg kg(-1), p.o., -1 h) suppressed Cg-induced pleural exudate accumulation by 84 and 77% and inflammatory cell influx by 66 and 47%, respectively. In contrast, celecoxib (CLX, 10 mg kg(-1), p.o., -1 h) or rofecoxib (RFX, 10 mg kg(-1) , p.o., -1 h) only reduced the Cg-induced pleural exudate volume by 44 and 40%, respectively, but had no significant effect over inflammatory cell influx. At the same doses used for pleurisy, DEX, INDO, CLX, RFX and SC-560 (a selective COX-1 inhibitor, 40 mg kg(-1), p.o., -1 h), inhibited the Cg-induced paw oedema by 49, 31, 21, 21 and 17%. DEX, INDO or SC-560 reduced the level of MPO by 71, 78 and 59%, while CLX or RFX produced a small, but significant increase (28 or 16%) in MPO activity. In the rat model of pleurisy, PGE2 levels in cell-free exudates were significantly attenuated by 91, 89, 57 and 65% in animals treated with DEX, INDO, CLX or RFX. In contrast, INDO reduced significantly the whole bloodTXB, synthesis (59%) while DEX and INDO reduced the pleural content of NOx significantly. Treatment of animals with CLX or RFX did not alter the content of pro-inflammatory cytokines IL-1beta or TNF-alpha in the pleural exudate, but CLX reduced IL-1beta levels in the rat paw tissue and RFX increased TNF-alpha in this tissue.. Together these results provide consistent evidence indicating that the selective COX-2 inhibitors CLX and RFX, in contrast to DEX, INDO or SC-560, despite reducing greatly the Cg-induced pleural exudation, PGE2 content and paw oedema have only partial acute anti-inflammatory properties in two different rat acute models of inflammation.

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dexamethasone; Dinoprostone; Edema; Indomethacin; Inflammation; Interleukin-1; Isoenzymes; Lactones; Male; Nitric Oxide; Peroxidase; Pleurisy; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Wistar; Sulfonamides; Sulfones; Thromboxane B2; Tumor Necrosis Factor-alpha

Atherosclerosis has features of an inflammatory disease. Because cyclooxygenase (COX)-2 is expressed in atherosclerotic lesions and promotes inflammation, we tested the hypotheses that selective COX-2 inhibition would reduce early lesion formation in LDL receptor-deficient (LDLR-/-) mice and that macrophage COX-2 expression contributes to atherogenesis in LDLR-/- mice.. Treatment of male LDLR-/- mice fed the Western diet with rofecoxib or indomethacin for 6 weeks resulted in significant reductions in atherosclerosis in the proximal aorta (25% and 37%) and in the aorta en face (58% and 57%), respectively. Rofecoxib treatment did not inhibit platelet thromboxane production, a COX-1-mediated process, but it significantly reduced the urinary prostacyclin metabolite 2,3-dinor-6-keto-PGF1alpha. Fetal liver cell transplantation was used to generate LDLR-/- mice null for expression of the COX-2 gene by macrophages. After 8 weeks on the Western diet, COX-2-/- --> LDLR-/- mice developed significantly less (33% to 39%) atherosclerosis than control COX-2+/+ --> LDLR-/- mice. In both the inhibitor studies and the transplant studies, serum lipids did not differ significantly between groups.. The present studies provide strong pharmacological and genetic evidence that COX-2 promotes early atherosclerotic lesion formation in LDLR-/- mice in vivo. These results support the potential of anti-inflammatory approaches to the prevention of atherosclerosis.

Topics: Animals; Arteriosclerosis; Blood Platelets; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Female; Indomethacin; Isoenzymes; Kinetics; Lactones; Lipids; Liver Transplantation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Receptors, LDL; RNA, Messenger; Sulfones; Thromboxane B2