Aspirin-induced increases in soluble IL-1 receptor type II concentrations in vitro and in vivo. (73/4641)

This study examined the influence of low-dose aspirin on interleukin (IL)-1alpha , IL-1 receptor antagonist (IL-1ra), and soluble receptor type II (sIL-1RII) secretion in vivo and in vitro. Blood mononuclear cells were isolated from healthy young men who ingested 81 mg of aspirin on alternate days for 2 weeks and from unmedicated controls. Aspirin had minor effects on ex vivo secretion of IL-1beta and no influence on IL-1ra. In contrast, unstimulated ex vivo secretion of sIL-1RII was over twice as high by cells from aspirin-treated subjects (1115+/-123 vs. 460+/-77 pg/mL, P = 0.02). Lipopolysaccharide-stimulated sIL-1RII secretion was influenced similarly. Plasma sIL-1RII concentrations were 23% higher in aspirin-treated subjects (10.2+/-0.6 vs. 8.4+/-0.3 ng/mL, P = 0.03). In addition, cells from unmedicated subjects cultured in vitro with aspirin (10 microg/mL) secreted significantly greater amounts of sIL-1RII. Thus, low-dose aspirin therapy may prevent inflammation by increasing soluble receptor secretion, thereby preventing IL-1 from binding target cells.  (+info)

Specific inhibition of cyclooxygenase-2 with MK-0966 is associated with less gastroduodenal damage than either aspirin or ibuprofen. (74/4641)

BACKGROUND: Compared with currently available NSAIDs (which inhibit COX-1 and COX-2 isoforms of cyclooxygenase), MK-0966 (a specific COX-2 inhibitor) is expected to cause less gastrointestinal toxicity. AIM: To compare the effect on the upper gastrointestinal mucosae of a high dose of MK-0966 with that of conventional doses of ibuprofen and aspirin. METHODS: Healthy subjects (n = 170; age range 18-54 years) with endoscopically normal gastric and duodenal mucosa were randomized to either MK-0966 250 mg q.d. (n = 51), ibuprofen 800 mg t.d.s. (n = 51), aspirin 650 mg q.d.s. (n = 17), or placebo (n = 51) in this 7-day, double-blind, parallel-group study. The mucosae were evaluated by endoscopy using a predefined scale; scores could range from 0 to 4. The primary end-point was the percentage of subjects who developed a mucosal score >/= 2 (i.e. the development of one or more erosions). To evaluate COX-1 activity, serum thromboxane B2 levels were determined in a subset of the population. RESULTS: The percentage of subjects who developed a mucosal score >/= 2 in the MK-0966 group (12%) was significantly lower (P < 0.001) than that in the ibuprofen (71%) and aspirin (94%) groups, and was similar to that in the placebo group (8%). Only ibuprofen and aspirin significantly (P < 0.0001) reduced baseline thromboxane B2 levels. All treatments were generally well tolerated. CONCLUSIONS: In this acute short-term endoscopic study, MK-0966 250 mg q.d. (a dose at least 10 times higher than that demonstrated to reduce the signs and symptoms of osteoarthritis) produced significantly less gastrointestinal mucosal damage than either ibuprofen 800 mg t.d.s. or aspirin 650 mg q.d.s. and was comparable to placebo in this regard.  (+info)

Comparison of antiplatelet activity of microencapsulated aspirin 162.5 Mg (Caspac XL), with enteric coated aspirin 75 mg and 150 mg in patients with atherosclerosis. (75/4641)

AIMS: A new formulation, low dose microencapsulated aspirin, permits slow absorption of aspirin and presystemic acetylation of platelet cyclo-oxygenase within the portal circulation, potentially avoiding deleterious effects on gastric and systemic prostaglandin synthesis. The objective of this study was to determine whether the administration of microencapsulated aspirin was as effective as enteric coated (EC) aspirin as an inhibitor of platelet function in patients with atherosclerosis. METHODS: One hundred and four patients were enrolled and randomised after a run in period of at least 14 days on aspirin EC 75 mg (day 0), to receive either microencapsulated aspirin 162.5 mg (n=34), aspirin EC 150 mg (n=36) or continue on aspirin EC 75 mg (n=34) for 28 days. Serum thromboxane B2 and collagen-induced platelet aggregation and release of 5-hydroxytryptamine (EC50 values) were measured on days 0 and 28. Aggregation/release EC50s were then repeated in the presence of a large dose of aspirin added in vitro to determine the EC50 at the maximum level of platelet inhibition. RESULTS: Median thromboxane B2 levels were low after 14 days run-in therapy with aspirin EC 75 mg, but significant further reductions were seen on day 28 in patients randomised to microencapsulated aspirin 162.5 mg (P=0.0368) and aspirin EC 150 mg (P=0.0004) compared with those remaining on aspirin EC 75 mg. Median EC50 s on day 28 showed small but significant increases from baseline (day 0) in aggregation in patients randomised to microencapsulated aspirin 162.5 mg (0.62-0.85, P=0.0482) and in both aggregation and release in patients randomised to aspirin EC 150 mg (0.95-1.20, P=0.0002, 8.4-11.7, P<0. 0001, respectively) signifying enhanced antiplatelet activity. No changes were seen in patients continuing on aspirin EC 75 mg. Results following addition of high dose aspirin in vitro suggest that mechanisms other than thromboxane synthesis may be operative in the long term effects of microencapsulated aspirin 162.5 mg and aspirin EC 150 mg over aspirin EC 75 mg. CONCLUSIONS: The results show good inhibition of thromboxane B2 synthesis and subsequent platelet activity by all preparations of aspirin, although both microencapsulated aspirin 162.5 mg and aspirin EC 150 mg are slightly more effective than aspirin EC 75 mg. A randomised trial is now required to determine whether microencapsulated aspirin is associated with fewer gastric side-effects.  (+info)

Chemoprevention of tobacco smoke-induced lung tumors in A/J strain mice with dietary myo-inositol and dexamethasone. (76/4641)

Male A/J strain mice were fed AIN-76A diet supplemented with myo-inositol/dexamethasone (10 g and 0.5 mg/kg diet) or acetylsalicylic acid (300 mg/kg) and exposed for 5 months to a mixture of sidestream and mainstream cigarette smoke at a concentration of 132 mg total suspended particulates/m3. After tobacco smoke exposure, they were allowed to recover for another 4 months in filtered air. In the animals fed AIN-75A diet alone or acetylsalicylic acid, the average number of tumors/lung was 2.1, whereas in the animals given the myo-inositol/dexamethasone diet, the average lung tumor multiplicity was 1.0 (P < 0.05). In animals exposed to filtered air, lung tumor multiplicities were 0.6 for animals fed AIN-76A or myo-inositol/dexamethasone and 1.2 for animals fed acetylsalicylic acid. It was concluded that the combination of myo-inositol and dexamethasone constitutes an effective chemopreventive regimen against tobacco smoke-induced lung tumorigenesis.  (+info)

Impact of cilostazol on restenosis after percutaneous coronary balloon angioplasty. (77/4641)

BACKGROUND: Restenosis after percutaneous transluminal coronary (balloon) angioplasty (PTCA) remains a major drawback of the procedure. We previously reported that cilostazol, a platelet aggregation inhibitor, inhibited intimal proliferation after directional coronary atherectomy and reduced the restenosis rate in humans. The present study aimed to determine the effect of cilostazol on restenosis after PTCA. METHODS AND RESULTS: Two hundred eleven patients with 273 lesions who underwent successful PTCA were randomly assigned to the cilostazol (200 mg/d) group or the aspirin (250 mg/d) control group. Administration of cilostazol was initiated immediately after PTCA and continued for 3 months of follow-up. Quantitative coronary angiography was performed before PTCA and after PTCA and at follow-up. Reference diameter, minimal lumen diameter, and percent diameter stenosis (DS) were measured by quantitative coronary angiography. Angiographic restenosis was defined as DS at follow-up >50%. Eligible follow-up angiography was performed in 94 patients with 123 lesions in the cilostazol group and in 99 patients with 129 lesions in the control group. The baseline characteristics and results of PTCA showed no significant difference between the 2 groups. However, minimal lumen diameter at follow-up was significantly larger (1.65+/-0.55 vs 1.37+/-0.58 mm; P<0.0001) and DS was significantly lower (34.1+/-17.8% vs 45.6+/-19. 3%; P<0.0001) in the cilostazol group. Restenosis and target lesion revascularization rates were also significantly lower in the cilostazol group (17.9% vs 39.5%; P<0.001 and 11.4% vs 28.7%; P<0. 001). CONCLUSIONS: Cilostazol significantly reduces restenosis and target lesion revascularization rates after successful PTCA.  (+info)

Local and systemic delivery of a stable aspirin-triggered lipoxin prevents neutrophil recruitment in vivo. (78/4641)

Aspirin (ASA) triggers a switch in the biosynthesis of lipid mediators, inhibiting prostanoid production and initiating 15-epi-lipoxin generation through the acetylation of cyclooxygenase II. These aspirin-triggered lipoxins (ATL) may mediate some of ASA's beneficial actions and therefore are of interest in the search for novel antiinflammatories that could manifest fewer unwanted side effects. Here, we report that design modifications to native ATL structure prolong its biostability in vivo. In mouse whole blood, ATL analogs protected at carbon 15 [15(R/S)-methyl-lipoxin A4 (ATLa1)] and the omega end [15-epi-16-(para-fluoro)-phenoxy-LXA4 (ATLa2)] were recoverable to approximately 90 and 100% at 3 hr, respectively, compared with a approximately 40% loss of native lipoxin A4. ATLa2 retains bioactivity and, at levels as low as approximately 24 nmol/mouse, potently inhibited tumor necrosis factor-alpha-induced leukocyte recruitment into the dorsal air pouch. Inhibition was evident by either local intra-air pouch delivery (approximately 77% inhibition) or systemic delivery by intravenous injection (approximately 85% inhibition) and proved more potent than local delivery of ASA. Rank order for inhibiting polymorphonuclear leukocyte infiltration was: ATLa2 (10 micrograms, i.v.) approximately ATLa2 (10 micrograms, local) approximately dexamethasone (10 micrograms, local) >ASA (1.0 mg, local). Applied topically to mouse ear skin, ATLa2 also inhibited polymorphonuclear leukocyte infiltration induced by leukotriene B4 (approximately 78% inhibition) or phorbol ester (approximately 49% inhibition), which initiates endogenous chemokine production. These results indicate that this fluorinated analog of natural aspirin-triggered lipoxin A4 is bioavailable by either local or systemic delivery routes and is a more potent and precise inhibitor of neutrophil accumulation than is ASA.  (+info)

Effect of aspirin and ifetroban on skeletal muscle blood flow in patients with congestive heart failure treated with Enalapril. Ifetroban Study Group. (79/4641)

OBJECTIVES: The purpose of this study was to determine the acute and chronic effects of cyclooxygenase inhibition with aspirin and thromboxane A2 receptor blockade with ifetroban on the chronic vasodilating effects of enalapril in the skeletal muscle circulation of patients with heart failure. BACKGROUND: Angiotensin-converting enzyme inhibition and antiplatelet therapy with aspirin independently reduce the risk for subsequent nonfatal coronary events in survivors of myocardial infarction. The safety of the combined administration of angiotensin-converting enzyme inhibitors and aspirin has been questioned due to their divergent effects on the vascular synthesis of vasodilating prostaglandins. METHODS: Forearm blood flow (ml/min/100 ml) at rest and during rhythmic handgrip exercise and after transient arterial occlusion was determined by strain gauge plethysmography before and 4 h and six weeks after combined administration of enalapril with either aspirin, ifetroban or placebo in a multicenter, double-blind, randomized trial of 62 patients with mild to moderate heart failure. RESULTS: Before randomization, forearm hemodynamics were similar in the three treatment groups except for increased resting forearm blood flow and decreased resting forearm vascular resistance in the aspirin group when compared with the placebo group. After combined administration of enalapril and study drug for 4 h and six weeks, changes from prerandomization values of mean arterial pressure, forearm blood flow and forearm vascular resistance at rest, during handgrip exercise and after transient arterial occlusion did not differ among the three treatment groups. CONCLUSIONS: These findings demonstrate that the vasodilating effects of enalapril in the skeletal muscle circulation of patients with heart failure are not critically dependent on prostaglandin pathways.  (+info)

Effect of acetylsalicylate on cardiac and muscular pain induced by intracoronary and intra-arterial infusion of bradykinin in humans. (80/4641)

OBJECTIVES: This study assessed the algesic activity of bradykinin (BK) in humans and the effects of acetylsalicylate on muscular and cardiac BK-induced pain. BACKGROUND: Bradykinin is released by the ischemic myocardium and may be involved in the genesis of ischemic pain. METHODS: Increasing doses of BK (from 30 to 960 ng/min) were randomly infused, for periods of 2 min each, into the iliac artery of 10 patients. The same protocol was repeated 30 min after the IV administration of 1 g of acetylsalicylate. In eight other patients with coronary artery disease, the same increasing doses of BK, for periods of 2 min each, were infused into the left coronary artery. The same protocol was repeated 30 min after the IV administration of 1 g of acetylsalicylate. Time to pain onset and maximal pain severity were obtained. RESULTS: Before acetylsalicylate administration, all patients experienced pain during intra-iliac infusion of BK. After acetylsalicylate, eight patients did not experience any pain during BK infusion (p = 0.0014), and in the two remaining patients, time to pain onset and maximal pain severity were similar to those recorded before acetylsalicylate. Before acetylsalicylate administration, all patients experienced pain similar to their habitual angina during intracoronary BK infusion. After acetylsalicylate, six patients did not experience any pain during BK infusion (p = 0.0098), whereas in the two remaining patients time to pain onset and maximal pain severity were similar to those recorded before acetylsalicylate. CONCLUSIONS: Intra-iliac infusion of BK causes muscular pain, and its intracoronary infusion in patients with coronary artery disease causes cardiac pain, which is similar to their habitual angina. The BK-induced pain is abolished or reduced by acetylsalicylate, thus suggesting that acetylsalicylate-sensitive mediators, such as prostaglandins, are involved in its pathogenesis.  (+info)