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PubMed2004

Aspirin resistance in stroke: 2004.

Aspirin is a well-established medication in the treatment of atherothrombotic vascular disease. However, despite aspirin treatment a substantial number of patients experience recurring ischaemic episodes. Aspirin resistance denotes those situations when it is unable to protect individuals from thrombotic complications, or when it fails to produce an anticipated effect in laboratory tests of platelet function. There are various laboratory techniques with which to evaluate the effectiveness of aspirin and other antiplatelet drugs. It has been estimated that in 5-60% of patients, aspirin does not achieve adequate efficacy in various measures of platelet activity. Some studies have revealed that vascular patients shown by laboratory tests to be aspirin-resistant are at an increased risk of major vascular events. The suggested mechanisms of aspirin resistance, among others, include genetic polymorphisms, alternate pathways of platelet activation, aspirin-insensitive thromboxane biosynthesis, drug interactions, or low aspirin dose. An increase in the dosage of aspirin or conversion to clopidogrel or clopidogrel plus aspirin might be beneficial in the management of those patients who are aspirin resistant. Additional work is required to improve and validate laboratory tests of platelet function, so that they may become useful tools for selecting the most appropriate antiplatelet therapy for an individual patient. Improvements in antiplatelet treatment strategies in the future should lead to a reduction in premature vascular events.

Aspirin↗
PubMed1999

Relationship of low-dose aspirin to GI injury and occult bleeding: a pilot study.

BACKGROUND: Low-dose aspirin is commonly used in patients with cardiovascular disease. However, little is known about the effect of aspirin on occult blood loss caused by gastrointestinal injury. Therefore, we studied endoscopic injury and fecal occult blood loss in patients ingesting different quantities of low-dose aspirin. METHODS: Forty healthy volunteers were enrolled in a randomized, double-blind, prospective, pilot endoscopic study. Each volunteer underwent 30 days of treatment with daily aspirin 30 mg, 81 mg, 325 mg, or placebo. Subjects completed fecal occult blood test cards before and at the end of treatment of two types: guaiac impregnated (Hemoccult and Hemoccult SENSA) and immunochemical (HemeSelect and FlexSure OBT). Each volunteer underwent upper endoscopy at baseline and after completing 30 days of study medication. RESULTS: Aspirin did not induce significant injury as determined by endoscopy when compared with placebo. Six of 30 volunteers taking aspirin developed erosions, whereas 1 of 10 subjects on placebo developed a new erosion (p = 0.66). Aspirin (325 mg) was associated with a higher mean symptom score than the lower aspirin dosages and the placebo group (p = 0.12). Only one subject taking aspirin (325 mg) had fecal occult blood on a single HemeSelect card. No subject had a positive fecal occult blood test with Hemoccult II, Hemoccult II SENSA, or FlexSure OBT cards. CONCLUSIONS: Aspirin in dosages commonly used for cardiovascular prophylaxis does not generally cause significant gastric or duodenal mucosal endoscopic lesions. In the absence of frank ulceration, low-dose aspirin does not result in positive fecal occult blood tests. Low-dose aspirin should not interfere with fecal occult blood testing and probably should not be stopped during stool collection.

Adult↗
PubMed2002

Resistance to aspirin in vitro at rest and during exercise in patients with angiographically proven coronary artery disease.

BACKGROUND: Acetylsalicylic acid, or aspirin, is widely used in secondary prevention of coronary artery diseases, but the inhibition of platelet aggregation is not uniform in all individuals. OBJECTIVE: To investigate the prevalence of aspirin resistance at rest and during exercise in coronary artery disease patients. MATERIALS AND METHODS: Fifty patients with stable coronary artery disease were prospectively studied. All patients received aspirin (75-300 mg/day for >1 month) and no other antiplatelet therapy. Aspirin resistance was studied, at rest and immediately after a stress test, using the standardized platelet function analyzer (PFA-100(R), Dade-Behring). Aspirin resistance was defined as a normal collagen/epinephrine closure time (<186 s). RESULTS: Ten patients (20%) were aspirin-resistant at rest. Out of the 40 patients who were aspirin-sensitive at rest, 9 (22%) were aspirin-resistant immediately after the exercise stress test. There were no differences in aspirin sensitivity regarding gender, age, diabetes, hypertension, dyslipidemia, platelet count, medical treatment or number of the coronary arteries involved. CONCLUSIONS: Aspirin resistance is detected, at rest, in 20% of our patients with stable coronary artery disease. Aspirin treatment does not seem to protect against exercise-induced platelet activation in 22% of such patients, despite aspirin sensitivity at rest.

Aged↗
PubMed2003

Aspirin use post-acute coronary syndromes: intolerance, bleeding and discontinuation.

BACKGROUND: While aspirin's secondary prevention benefit is clear, prior reports indicate that 19-83% of eligible patients may not use aspirin chronically. METHODS: We investigated intolerance and bleeding while on aspirin and aspirin discontinuation using 5337 post-acute coronary syndrome patients considered appropriate for chronic antiplatelet therapy who were randomly assigned to aspirin in SYMPHONY and 2nd SYMPHONY and followed for 94 (64,157) days. Multivariable logistic regression models tested associations between baseline characteristics and aspirin discontinuation and bleeding. RESULTS: Nearly 18% of patients discontinued study aspirin; 48% subsequently used open-label aspirin and 5% other antiplatelet or anticoagulant therapy. Black race, recurrent ischemia, hypertension, chronic obstructive pulmonary disease, lighter weight, shorter time to treatment and use of non-steroidal anti-inflammatory agents, diuretics, and digitalis were independently associated with early discontinuation. Early discontinuation was less likely in Eastern Europe, Latin America and Asia. Although major or minor bleeding was common (12.6%), only 1.0% of aspirin-treated patients were reported to discontinue due to bleeding. Gastrointestinal (10.5%) and puncture site (7.6%) were the most common bleeding locations. Bleeding risk was associated with lower estimated creatinine clearance, shorter time to treatment, smoking, Killip class >II, higher systolic blood pressure, and use of aspirin or heparin prior to starting study aspirin. CONCLUSIONS: Despite early initiation and close follow-up, more than 9% of aspirin-treated patients discontinued therapy early and remained off treatment. Addressing the factors associated with both bleeding and discontinuation during chronic therapy is necessary to improve adherence to this inexpensive, life-saving therapy.

Acute Disease↗
PubMed2002

Effect of aspirin on vasodilation to bradykinin and substance P in patients with heart failure treated with ACE inhibitor.

AIMS: We wanted to examine some of the mechanisms by which aspirin might be responsible for counteraction of the effects of ACE inhibitors. Aspirin has been reported to counteract the effects of ACE inhibitors in patients with heart failure. Despite this, there is little evidence on what the mediator of such an effect might be, although there is some evidence to implicate bradykinin and, perhaps, substance P. METHODS: Twelve patients with congestive heart failure treated with an ACE inhibitor were studied on two occasions, after abstaining from aspirin for 14 days, and after 14 days of aspirin 150 mg once daily. Forearm blood flow was measured by venous occlusion plethysmography during intrabrachial infusions of bradykinin and substance P, before and after intrabrachial aspirin. RESULTS: Bradykinin caused profound vasodilation (peak 390%, 95% confidence intervals (CI) 300, 480%; P < 0.01), substance P slightly less (peak 222%, 95% CI 162, 283%; P < 0.01). Intra-brachial aspirin had no effect on its own. The response to bradykinin was unchanged by intrabrachial aspirin (peak 404%, 95% CI 304, 504%) or oral aspirin (peak 320%, 95% CI 209, 431%; P = 0.2). The response to substance P was unchanged by intrabrachial aspirin (peak 226%, 95% CI 171, 281%) or oral aspirin (peak 220%, 95% CI 142, 297%; P = 0.86). CONCLUSIONS: Aspirin has no effect on the vasodilator response to bradykinin and substance P in patients with heart failure treated with an ACE inhibitor. Neither bradykinin nor substance P is likely to contribute to the reported interaction between aspirin and ACE inhibitors.

Aged↗
PubMed2004

Cardiovascular prophylaxis with aspirin: costs of supply and management of upper gastrointestinal and renal toxicity.

AIMS: To determine the cost to the NHS of prescribed low-dose aspirin. METHODS: This was a population based observational cohort study. Patients from Tayside Scotland (17 244 new users of dispensed aspirin each with 10 matched comparators) were included. A pragmatic analysis totalled costs from the start to end of the study and compared these with a matched cohort of aspirin nonusers to estimate excess costs. Fastidious analyses were done of subjects with no prior history of upper gastrointestinal (UGI) or renal disease where the cost that occurred during aspirin exposure, the 30 days following aspirin exposure and subsequent nonexposure was calculated adjusting for risk factors in each period. RESULTS: Subjects took aspirin for only 1.18 of the 2.53 years follow-up (47% compliance). Aspirin use cost an additional 49.86 UK pounds per year (pragmatic analysis) made up of 1.96 UK pounds for aspirin tablets (4%), 5.49 UK pounds for dispensing costs (11%), 24.60 UK pounds for UGI complications (49%) and 17.81 UK pounds for renal complications (36%). The costs for managing complications were substantially lower in the fastidious analysis (2.66 UK pounds for UGI complications and 2.92 UK pounds for renal complications). Assuming that the antiplatelet trial meta-analysis is an accurate assessment of the benefits of aspirin, the costs of preventing one vascular event lay between 62 500 UK pounds (primary prevention, pragmatic analysis) and 867 UK pounds (secondary prevention, fastidious analysis). These costs may be underestimates due to the low compliance observed. CONCLUSIONS: Compliance with aspirin was poor. Serious adverse events were uncommon but despite this aspirin cost the NHS between 6 and 25 times the cost of aspirin tablets due to dispensing costs and the cost of managing adverse effects.

Acute Kidney Injury↗
PubMed2002

Cyclooxygenase-2-derived lipoxin A4 increases gastric resistance to aspirin-induced damage.

BACKGROUND & AIMS: Cyclooxygenase-2 (COX-2) has been implicated as contributing to mucosal defense. Acetylation of COX-2 by aspirin can result in production of an antiinflammatory substance, 15(R)-epi-LXA4. We determined whether aspirin-triggered lipoxin (LX) production via COX-2 diminishes aspirin-induced damage in the rat stomach. METHODS: Rats were treated with aspirin plus or minus celecoxib or rofecoxib. Gastric generation of LXA4 was measured. Effect of exogenous LXA4 or an LXA4 receptor antagonist on gastric resistance to aspirin-induced damage was examined. Aspirin-induced leukocyte adherence in mesenteric venules, and the effects of LXA4, were examined by intravital microscopy. RESULTS: Celecoxib and rofecoxib significantly increased the severity of aspirin-induced gastric damage. Aspirin rapidly up-regulated COX-2 expression in the stomach and caused a significant increase in gastric 15(R)-epi-LXA4 production, which was abolished by celecoxib. LXA4 dose dependently (0.25-2.5 microg/kg, intraperitoneally) reduced the severity of aspirin-induced gastric damage and suppressed aspirin-induced leukocyte adherence, whereas an LXA4 antagonist had the opposite effects. CONCLUSIONS: Aspirin administration results in elevated production of 15(R)-epi-LXA4 via COX-2. LXA4 exerts very potent protective actions on the gastric mucosa. Co-administration of aspirin and a selective COX-2 inhibitor results in substantially more severe gastric injury than is produced with either agent alone.

Animals↗
PubMed2001

Effect of low-dose aspirin in combination with stable fish oil on whole blood production of eicosanoids.

The effect of a combination of aspirin and fish oil on eicosanoids was studied. Four subjects were given 37.5 mg aspirin orally, and 6 weeks later they received a natural, stable fish oil daily for 1 week before taking the same single dose of aspirin. Blood samples for determination of whole blood production of eicosanoids were taken before and after each experimental period. Serum thromboxane A(2)was decreased by 40% (P<0.05) after aspirin alone, but by 62% (P<0.01) after fish oil + aspirin. Serum prostacyclin (measured as 6-keto PGF(1a)) was decreased by aspirin in both cases. The sum of 6-keto PGF(1a)and its equipotent fish oil-derived analogue Delta(17)-6-keto PGF(1a)was reduced after aspirin intake (55%, NS), but after fish oil + aspirin the reduction was smaller (33%, NS). Leukotriene B(4)was increased by 19% (P<0.05) after aspirin, and decreased by 69% (P<0.05) after fish oil + aspirin. A combination of stable fish oil and aspirin thus improves the eicosanoid pattern more than aspirin alone.

6-Ketoprostaglandin F1 alpha↗
PubMed2002

Warfarin, aspirin, or both after myocardial infarction.

BACKGROUND: The role of antithrombotic therapy in secondary prevention after myocardial infarction is well established. Although the available literature suggests that warfarin is superior to aspirin, aspirin is currently the more widely used drug. We studied the efficacy and safety of warfarin, aspirin, or both after myocardial infarction. METHODS: In a randomized, multicenter trial in 3630 patients, 1216 received warfarin (in a dose intended to achieve an international normalized ratio [INR] of 2.8 to 4.2), 1206 received aspirin (160 mg daily), and 1208 received aspirin (75 mg daily) combined with warfarin (in a dose intended to achieve an INR of 2.0 to 2.5). The mean duration of observation was four years. RESULTS: The primary outcome, a composite of death, nonfatal reinfarction, or thromboembolic cerebral stroke, occurred in 241 of 1206 patients receiving aspirin (20.0 percent), 203 of 1216 receiving warfarin (16.7 percent; rate ratio as compared with aspirin, 0.81; 95 percent confidence interval, 0.69 to 0.95; P=0.03), and 181 of 1208 receiving warfarin and aspirin (15.0 percent; rate ratio as compared with aspirin, 0.71; 95 percent confidence interval, 0.60 to 0.83; P=0.001). The difference between the two groups receiving warfarin was not statistically significant. Episodes of major, nonfatal bleeding were observed in 0.62 percent of patients per treatment-year in both groups receiving warfarin and in 0.17 percent of patients receiving aspirin (P<0.001). CONCLUSIONS: Warfarin, in combination with aspirin or given alone, was superior to aspirin alone in reducing the incidence of composite events after an acute myocardial infarction but was associated with a higher risk of bleeding.

Aged↗
PubMed2000

Ex vivo--in vitro interaction between aspirin, clopidogrel, and the glycoprotein IIb/IIIa inhibitors abciximab and SR121566A.

OBJECTIVES: To assess the interaction between aspirin and clopidogrel in healthy male volunteers and the interaction of the glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors abciximab and SR121566A with blood from those pretreated subjects (ex vivo-in vitro). METHODS: Aspirin (300 mg/day), clopidogrel (75 mg/day), or the combination of both drugs were administered orally for 8 days. Group 1 (n = 5) started with aspirin and group 2 (n = 5) with clopidogrel. From day 4 to day 8, subjects of both groups received the combined treatment. Blood from these subjects was spiked with abciximab (0.5 and 1.5 microg x mL(-1)) and SR121566A (31 and 62 ng x mL(-1)). RESULTS: In vivo, average bleeding times were 6.8 minutes at baseline, 20.3 minutes for clopidogrel alone (P < .01), 10.9 minutes for aspirin alone (difference not significant), and 24.0 minutes (P < .01) for the combined treatment. Fibrinogen binding to the platelet GPIIb/IIIa receptor was reduced for aspirin to 69% (difference not significant), to 63% for clopidogrel (difference not significant), and to 63% for the clopidogrel plus aspirin combination (P < .01). CD62 expression as a marker of platelet granular secretion was reduced to 66% by clopidogrel (P < .01) and to 41% by the combination of clopidogrel and aspirin; aspirin alone had no effect. In vitro, with pretreatment with aspirin and clopidogrel, inhibitory effects of the GPIIb/IIIa inhibitors on fibrinogen binding were additive to changes observed with aspirin or clopidogrel alone. No effect on CD62 expression was observed with either GPIIb/IIIa inhibitor. Aspirin and clopidogrel reinforced effects of the GPIIb/IIIa inhibitors on adenosine diphosphate (5 micromol/L)-induced aggregation in an additive manner, a supra-additive effect was observed with collagen (2 microg x mL(-1))-induced aggregation. CONCLUSION: The augmentation of the antiaggregatory effects of GPIIb/IIIa inhibitors by aspirin and clopidogrel and the lack of antisecretory effects of GPIIb/IIIa inhibitors may favor their combination with clopidogrel.

Abciximab↗
PubMed2003

Isozyme-specific induction of low-dose aspirin on cytochrome P450 in healthy subjects.

OBJECTIVE: This study was designed to define the effect of low-dose aspirin administration on the activity of cytochrome P450 (CYP) in normal human subjects. METHODS: Aspirin, 50 mg daily, was given for 14 days to 18 nonsmoking healthy male volunteers. A modified 5-drug cocktail procedure consisting of caffeine, mephenytoin, metoprolol, chlorzoxazone, and midazolam was performed to simultaneously assess in vivo activity of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and CYP3A, respectively. The activities were assessed on 4 occasions including at baseline, after 7 and 14 daily doses of aspirin, and at 7 days after discontinuation of aspirin. Concentrations of parent drugs and corresponding metabolites in biologic samples were assayed by reversed-phase HPLC. RESULTS: Both 7-day and 14-day aspirin intake increased the activity of CYP2C19 significantly, as indicated by 4-hydroxymephenytoin urinary recovery (P <.001). Induction of low-dose aspirin on CYP2C19 was time-dependent. CYP3A activity indices increased moderately but significantly by both 7-day and 14-day aspirin treatment (P <.05), but the percentage changes in CYP3A activity indices were not significant. Low-dose aspirin had no effect on CYP1A2, CYP2D6, and CYP2E1 in vivo activity by either 7-day or 14-day treatment. CONCLUSIONS: The effect of low-dose aspirin on CYPs was enzyme-specific. Both 7-day and 14-day low-dose aspirin induced the in vivo activities of CYP2C19 but did not affect the activities of CYP1A2, CYP2D6, and CYP2E1. The effect of low-dose aspirin on CYP3A activity awaits further confirmation. When low-dose aspirin is used in combination with drugs that are substrates of CYP2C19, doses of the latter should be adjusted to ensure their efficacy.

Administration, Oral↗
PubMed2001

Characterization and clinical course of patients not receiving aspirin for acute myocardial infarction: results from the MITRA and MIR studies.

BACKGROUND: Clinical trials have shown the efficacy of aspirin for acute myocardial infarction (AMI). However, not all patients receive aspirin for AMI. The aim of this study was to provide information on characteristics and clinical course of patients not treated with aspirin for AMI. METHODS: We analyzed the data of the Myocardial Infarction Registry (MIR) and the Maximal Individual Therapy of Acute Myocardial Infarction (MITRA) registry. MITRA and MIR were prospective multicenter registries of patients with ST segment elevation myocardial infarction in Germany. RESULTS: Of 22,572 patients registered from 1994 to 1998, 1767 (7.8%) did not receive aspirin within the first 48 hours after admission. Multivariate analysis revealed two main factors associated with withholding aspirin for AMI: relative contraindications to aspirin (gastric ulcer [odds ratio (OR) 4.9, 95% confidence interval (CI) 3.7-5.7], renal insufficiency [OR 1.4, 95% CI 1.1-1.8]), and critical clinical state at admission (cardiogenic shock [OR 1.5, 95% CI 1.2-2.1] and prehospital resuscitation [OR 1.8, 95% CI 1.4-2.2]). In addition, these patients were significantly less likely to receive reperfusion therapy and adjunctive medical therapy such as beta-blockers and angiotensin-converting enzyme inhibitors. In-hospital mortality after adjustment for baseline characteristics was 27.2% in patients without aspirin compared with 11.1% in patients treated with aspirin. CONCLUSIONS: Only a minority of AMI patients (7.8%) did not receive aspirin. Relative contraindications to aspirin and a critical clinical state at admission were the main factors associated with withholding aspirin for AMI. Even after adjustment for patient characteristics, the mortality of patients without aspirin was almost three times higher.

Aged↗
PubMed1992

Adverse effects of aspirin in the treatment of asymptomatic carotid artery stenosis. The VA Cooperative Asymptomatic Carotid Artery Stenosis Study Group.

We prospectively analyzed adverse effects of aspirin in a multicentered cooperative study undertaken to determine the role of endarterectomy in the treatment of asymptomatic carotid artery stenosis. Persons with active peptic ulcer disease or known intolerance to aspirin were excluded from the study. Patients initially received 650 mg aspirin twice daily. After a 54-month recruitment period, 444 patients in 11 centers were followed up for as many as 8 years (mean 47.9 +/- 27.9 months). Patients intolerant to 650 mg aspirin twice daily could be switched to enteric-coated aspirin or "low-dose" aspirin (80 to 325 mg daily). At the conclusion of the study, we performed a cross-sectional analysis of aspirin usage and complications. Overall, there were 757 episodes reported wherein adjustments in study medications were made, including cessation and change in formulation or dosage. At the conclusion of the study, at the time of death, or at occurrence of a neurologic end point, 16% of patients were off medication entirely, 51% had been converted to enteric-coated aspirin, and only 33% were taking regular aspirin with 27% of those having been placed on a reduced dosage. Adverse reactions were ascertained from 4954 patient visit records. In all there were a total of 837 adverse reactions reported, or one in every 5.9 visits. The most frequently reported reaction was heartburn or stomach pain for which 372 episodes were reported in 184 (42%) patients. Nausea or vomiting occurred on 79 occasions in 58 patients, and bloody stools were reported 52 times in 41 patients. We conclude that high-dose aspirin therapy for asymptomatic carotid artery stenosis is poorly tolerated and that adverse reactions even to low-dose enteric-coated aspirin are common even in patients screened for aspirin intolerance.

Aged↗
PubMed2004

Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial.

There is increasing evidence that aspirin initiates biosynthesis of novel antiinflammatory mediators by means of interactions between endothelial cells and leukocytes. These mediators are classified as aspirin-triggered 15-epi-lipoxins. Such compounds may account at least in part for aspirin's clinical benefits, which are distinct from the well appreciated action of aspirin as a platelet inhibitor. Here, we addressed whether aspirin-triggered 15-epilipoxinA4 (ATL) formation is aspirin-dependent in humans and its relationship to aspirin's antiplatelet activity. We conducted a randomized clinical trial among 128 healthy subjects allocated to placebo or to 81-, 325-, or 650-mg daily doses of aspirin for 8 weeks. Plasma thromboxane (TX)B2, an indicator of platelet reactivity, and ATL were assessed from blood collected at baseline and at 8 weeks. Plasma ATL levels significantly increased in the 81-mg aspirin group (0.25 +/- 0.63 ng/ml, P = 0.04), with borderline increases in the 325-mg group (0.16 +/- 0.71 ng/ml) and no apparent significant changes in the 650-mg group (0.01 +/- 0.75 ng/ml, P = 0.96). When ATL and TXB2 were compared, levels changed in a statistically significant and opposite direction (P < 0.01) for all three aspirin doses. These results demonstrated that low-dose aspirin (81 mg daily) initiates production of antiinflammatory ATL opposite to the inhibition of TX. Monitoring ATL may represent a simple clinical parameter to verify an individual's vascular leukocyte antiinflammatory response with low-dose aspirin treatment. These results also emphasize the importance of cell-cell interactions in the modulation of hemostatic, thrombotic, and inflammatory processes.

Adult↗
PubMed2002

Chronic treatment with nitric oxide-releasing aspirin reduces plasma low-density lipoprotein oxidation and oxidative stress, arterial oxidation-specific epitopes, and atherogenesis in hypercholesterolemic mice.

The effects of chronic treatment with nitric oxide-containing aspirin (NO-aspirin, NCX-4016) in comparison with regular aspirin or placebo on the development of a chronic disease such as atherosclerosis were investigated in hypercholesterolemic low-density lipoprotein (LDL)-receptor-deficient mice. Male mice were assigned randomly to receive in a volume of 10 ml/kg either placebo (n = 10), 30 mg/kg/day NO-aspirin (n = 10), or 18 mg/kg/day of regular aspirin (n = 10). After 12 weeks of treatment, the computer-assisted imaging analysis revealed that NO-aspirin reduced the aortic cumulative lesion area by 39.8 +/- 12.3% compared with that of the placebo (P < 0.001). Regular aspirin did not reduce significantly aortic lesions (-5.1 +/- 2.3%) compared with the placebo [P = 0.867, not significant (NS)]. Furthermore, NO-aspirin reduced significantly plasma LDL oxidation compared with aspirin and placebo, as shown by the significant reduction of malondialdehyde content (P < 0.001) as well as by the prolongation of lag-time (P < 0.01). Similarly, systemic oxidative stress, measured by plasma isoprostanes, was significantly reduced by treatment with NCX-4016 (P < 0.05). More importantly, mice treated with NO-aspirin revealed by immunohistochemical analysis of aortic serial sections a significant decrease in the intimal presence of oxidation-specific epitopes of oxLDL (E06 monoclonal antibody, P < 0.01), and macrophages-derived foam cells (F4/80 monoclonal antibody, P < 0.05), compared with placebo or aspirin. These data indicate that enhanced NO release by chronic treatment with the NO-containing aspirin has antiatherosclerotic and antioxidant effects in the arterial wall of hypercholesterolemic mice.

Animals↗
PubMed2000

Effects of continuous supplementations of ascorbic acid, aspirin, vitamin E and selenium on some haematological parameters and serum superoxide dismutase level in broiler chickens.

1. This study was conducted using male broiler chickens to determine the effects of ascorbic acid, aspirin, ascorbic acid+aspirin, vitamin E+selenium and ascorbic acid+aspirin+vitamin E+selenium supplementations on haematological parameters and serum superoxide dismutase concentration. 2. One hundred and twenty day-old male Hubbunt broiler chicks were randomly divided into 6 experimental groups of 20 chicks each and placed in different pens. Groups 2, 3, 4, 5 and 6 were given a diet supplemented with ascorbic acid, aspirin (in water), ascorbic acid+aspirin, vitamin E+selenium and ascorbic acid+aspirin+vitamin E+selenium, respectively for 45 d while group 1 was given a commercial broiler diet. 3. There was no significant effect of ascorbic acid, aspirin, ascorbic acid+aspirin, vitamin E+selenium supplementations on any of the haematological parameters (red blood cell, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin concentration, mean corpuscular haemoglobin) in broilers but ascorbic acid+aspirin+vitamin E+selenium supplementation significantly decreased the white blood cell counts. 4. In addition to this, ascorbic acid, aspirin, ascorbic acid+aspirin and ascorbic acid+aspirin+vitamin E+selenium supplementations had no significant effect on the serum superoxide dismutase level, but vitamin E+selenium supplementation increased the serum superoxide dismutase level.

Animals↗
PubMed2004

15-epi-lipoxin A4-mediated induction of nitric oxide explains how aspirin inhibits acute inflammation.

The established model for the mechanism of action of aspirin is the inhibition of prostaglandin synthesis. However, this has never fully explained aspirin's repertoire of antiinflammatory properties. We found in acute pleuritis that aspirin, but not salicylate, indomethacin, or piroxicam, increased plasma nitric oxide (NO), which correlated with a reduction in inflammation. Inhibiting aspirin-elicited NO pharmacologically in this model nullified the antiinflammatory effects of aspirin. Moreover, aspirin was not antiinflammatory in either constitutive (eNOS) or inducible NO synthase (iNOS) knockout mice with IL-1beta-induced peritonitis. It transpires that aspirin generates NO through its unique ability to trigger the synthesis of 15-epi-lipoxin A(4). Aspirin and 15-epi-lipoxin A(4) were shown to inhibit leukocyte trafficking in an NO-dependent manner using intravital microscopy on IL-1beta-stimulated mouse mesentery. Not only did aspirin inhibit leukocyte-endothelial interaction in a manner similar to NO in wild-type mice but both aspirin and 15-epi-lipoxin A(4) had markedly reduced effects on leukocyte-endothelial cell adherence in eNOS- and iNOS-deficient mice compared with wild type. Collectively, these data suggest that aspirin triggers the synthesis of 15-epi-lipoxin A(4), which increases NO synthesis through eNOS and iNOS. This aspirin-elicited NO exerts antiinflammatory effects in the microcirculation by inhibiting leukocyte-endothelium interactions.

Animals↗
PubMed1991

Effect of dipyridamole alone and in combination with aspirin on whole blood platelet aggregation, PGI2 generation, and red cell deformability ex vivo in man.

STUDY OBJECTIVE: The aim was to investigate the effects of dipyridamole, aspirin, and a combination of dipyridamole plus aspirin on platelet aggregation in whole blood, PGI2 generation, and red cell deformability ex vivo. SUBJECTS: were 16 male volunteers, aged 22-39 years, mean age, 26.6 years. DESIGN: This was a randomised, double blind, placebo controlled trial. The volunteer received each of the following treatments 10 days apart: dipyridamole 200 mg; aspirin 300 mg; dipyridamole 200 mg plus aspirin 300 mg; matched placebos. MEASUREMENTS AND MAIN RESULTS: Blood was taken for platelet function tests, PGI2 metabolite assay, and red cell deformability before and 2 h after the trial dose was taken. Platelet aggregation was quantified by measuring the fall in single platelet count after stimulation with 2 micrograms.ml-1 collagen or 50 nM platelet activating factor (PAF), or by rollermixing aliquots of blood to initiate spontaneous aggregation. The platelet function tests were completed at 37 degrees C within 10 min of venepuncture. The stable metabolite of PGI2, 6-keto PGF1 alpha, was measured in serum. There was inhibition of spontaneous platelet aggregation by dipyridamole (p less than 0.004), aspirin (p less than 0.005), and the combination of dipyridamole plus aspirin (p less than 0.0001) as compared with placebo. PAF induced platelet aggregation was inhibited by dipyridamole (p less than 0.002) and the combination of dipyridamole plus aspirin (p less than 0.0001) but aspirin alone had no inhibitory effect. Collagen induced platelet aggregation was inhibited by all three treatments: dipyridamole (p less than 0.06), aspirin (p less than 0.0001), and the combination of dipyridamole plus aspirin (p less than 0.0001). PGI2 generation was markedly inhibited by aspirin (p less than 0.0001) and the combination doses (p less than 0.0001) but was unaffected by dipyridamole alone. Of the three active treatments, only dipyridamole alone significantly (p less than 0.001) increased red cell deformability; there was a modest decrease in red cell deformability with aspirin. CONCLUSIONS: The results with PAF support the view that dipyridamole inhibits platelet activation by more than one mechanism; the effect on collagen induced and spontaneous platelet aggregation suggests that the effect of the combination doses is additive and that on red cell deformability the synergy is negative.

6-Ketoprostaglandin F1 alpha↗