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PubMed1995

In vitro release of arachidonic acid metabolites, glutathione peroxidase, and oxygen-free radicals from platelets of asthmatic patients with and without aspirin intolerance.

BACKGROUND: An abnormal platelet release of oxygen-free radicals has been described in acetylsalicylic acid (aspirin)-induced asthma, a finding which might suggest the existence of an intrinsic, specific platelet abnormality of arachidonic acid metabolism in these patients. The objective of this study was to evaluate platelet arachidonic acid metabolism in asthmatic patients with or without intolerance to aspirin. METHODS: Thirty subjects distributed into three groups were studied: group 1, 10 healthy subjects; group 2, 10 asthmatic patients with aspirin tolerance; and group 3, 10 aspirin-intolerant asthmatics. Platelets were isolated from blood, preincubated with 3H-arachidonic acid for 30 minutes and then incubated for 10 minutes with platelet activating factor (PAF) and aspirin. Cyclo-oxygenase (thromboxane, PGE2, PGF2 alpha, and HHT) and lipoxygenase (12-HETE) arachidonic acid metabolites were measured by high pressure liquid chromatography. Release of oxygen free radicals after incubation with PAF and aspirin was measured by chemiluminescence. Platelet levels of glutathione peroxidase (GSH-Px) were also measured using spectrophotometry. RESULTS: Platelets from aspirin-intolerant asthmatic patients produced higher quantities of arachidonic acid metabolites than the control group at baseline conditions. This increase was significant only for lipoxygenase products. No differences were found amongst the three groups in the response of arachidonic acid metabolism to PAF and aspirin. Incubation with aspirin but not with PAF caused an increase in oxygen-free radical production in aspirin-intolerant patients whereas in aspirin-tolerant patients PAF, rather than aspirin, was the more potent stimulus for oxygen-free radical production. No differences in GSH-Px levels were found amongst the three groups. CONCLUSIONS: These results suggest that the platelet lipoxygenase pathway is activated in aspirin-intolerant patients and that the production of oxygen-free radicals may differentiate aspirin-tolerant from aspirin-intolerant asthmatic subjects. Our study, however, does not support the hypothesis that an increase in lipoxygenase products may be responsible for oxygen-free radical production. Moreover, a lowered platelet GSH-Px activity does not seem to be involved in this phenomenon.

Adult↗
PubMed2005

Aspirin has a gender-dependent impact on antiinflammatory 15-epi-lipoxin A4 formation: a randomized human trial.

OBJECTIVE: Aspirin blocks thromboxane production that contributes to its well-appreciated antiplatelet action. Aspirin also initiates the biosynthesis of novel antiinflammatory mediators from arachidonic acid, namely aspirin-triggered 15-epi-lipoxin A4. We recently conducted a double-blinded clinical trial with healthy subjects in whom low-dose aspirin (81 mg daily) significantly increased aspirin-triggered 15-epi-lipoxin A4 and concomitantly inhibited thromboxane. Here, we assessed whether plasma aspirin-triggered 15-epi-lipoxin A4 was age or gender dependent in subjects taking low-dose aspirin. METHODS AND RESULTS: A total of 128 subjects were allocated to: placebo, 81, 325, or 650 mg daily aspirin for an 8-week period. Plasma thromboxane B2 and aspirin-triggered 15-epi-lipoxin A4 were assessed from blood collected at baseline and the conclusion of the trial. We then performed a post-trial analysis in the group receiving low-dose aspirin. In female subjects, we found a positive correlation between age and aspirin-triggered 15-epi-lipoxin A4(increase of 0.37 ng/mL per decade), and a negative correlation was observed in men (decrease of 0.29 ng/mL per decade). These trends were significantly different from each other (P=0.045). CONCLUSIONS: Low-dose aspirin has a gender-specific impact on aspirin-triggered 15-epi-lipoxin A4 production, which may contribute to the gender-dependent clinical benefits of aspirin. Also, they may provide a molecular rationale for low-dose aspirin therapies in elderly women to reduce inflammation-related disorders.

Acetylation↗
PubMed1992

Effects of low-to-high doses of aspirin on platelet aggregability and metabolites of thromboxane A2 and prostacyclin.

BACKGROUND AND PURPOSE: The purpose of this study was to compare the effects of low-to-high doses of aspirin on platelet aggregability determined by different methods and on the metabolism of thromboxane A2 and prostacyclin. METHODS: We administered increasing doses (40, 320, and 1,280 mg/day) of aspirin to 19 poststroke patients and studied the differences in 1) the changes in platelet aggregability depending on the methods of evaluation and 2) the concentrations of prostaglandin metabolites in the blood and urine. RESULTS: Aggregation of platelet-rich plasma induced by a strong stimulus (10 microM ADP) was significantly reduced after 40 mg/day aspirin (p less than 0.005), and this reduction was similar to that after higher aspirin doses. In contrast, aggregation of platelet-rich plasma induced by weaker stimuli (1 and 5 microM ADP) decreased less significantly after 40 mg/day aspirin compared with that after higher aspirin doses. The serum thromboxane B2 generated after ex vivo incubation was reduced significantly (by 85%) after 40 mg/day aspirin and decreased further after 320 mg/day (by 96%) and 1,280 mg/day (by greater than 99%) of aspirin. The urinary 11-dehydro-thromboxane B2 concentration decreased less significantly after 40 mg/day aspirin (by 42%) compared with that after 320 mg/day (by 78%) and 1,280 mg/day (by 91%) aspirin doses. The urinary concentration of 2,3-dinor-6-keto-prostaglandin F1 alpha did not decrease after 40 mg/day aspirin but decreased significantly after higher doses of aspirin. CONCLUSIONS: These findings suggest that different doses of aspirin may be necessary to prevent thrombogenesis induced by different triggers of different strengths and that 40 mg/day aspirin is able to inhibit a large proportion of maximum thromboxane A2 release provoked acutely, with the prostaglandin I2 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Attenuation of aspirin analgesia by calcium loading in healthy subjects.

To clarify the mechanism of aspirin analgesia, the relationship among analgesic and hypocalcemic effects and pharmacokinetics of aspirin was investigated in 20 healthy subjects at 20-23 years old. Four experimental groups were made, that is, (1) aspirin 1.0 g, (2) aspirin 1.0 g + calcium gluconate 1.5 g X 2, (3) calcium gluconate 1.5 g X 2, (4) control (placebo). Calcium gluconate was administered orally twice, that is, 30 and 90 min after oral administration of aspirin. The experiments were carried out under a double blind method. As an analgesic test, the ultrasonic method was used. Aspirin (1.0 g) caused a significant analgesia, the effect reaching the maximum at 90 min and prolonging for about 3 h. Simultaneously, plasma calcium level significantly decreased and kept going down, at least, until 180 min after administration of aspirin. However, when calcium gluconate was loaded at 30 and 90 min after administration of aspirin, both the analgesic and hypocalcemic effects of aspirin were significantly inhibited. The plasma aspirin concentration reached a maximum 30-60 min after administration of aspirin in both groups: aspirin alone and aspirin with calcium gluconate. On the other hand, plasma salicylic acid concentration kept increasing up to 180 min after administration of aspirin in either group. The plasma aspirin and salicylic acid levels in both groups were similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2004

Aspirin in cardiovascular disorders. What is the optimum dose?

Clinical trials of aspirin (acetylsalicylic acid) for cardiovascular disorders have employed doses defined for other pharmacological effects of the drug (such as analgesic effects). Antioxidant and anti-inflammatory mechanisms with different dose-response relationships may contribute to the clinical effect of aspirin in cardiovascular disease. The optimal aspirin dose remains uncertain. Although the difference between 325 mg/day and 81 mg/day of aspirin sounds trivial, finding an optimal aspirin dose has enormous potential to reduce ischemic events. Large aspirin doses have not been associated with proportionally greater benefit. For patients with ischemic heart disease, overall consensus defines a range between 75 and 160 mg/day for the secondary prevention of myocardial infarction, stroke, and vascular death. Any benefit of aspirin must be measured against its adverse effects, principally gastrointestinal hemorrhage. The potential for adverse bleeding events may be lower with a 81mg dose, while maintaining clinical benefit. Although current aggregate data is reassuring about aspirin administration, it is increasingly clear that existing aspirin studies are insufficient to conclusively determine an optimal aspirin dose. Platelets can be activated by pathways that are not blocked by aspirin, and the dose of aspirin needed to fully suppress platelet aggregation may be higher in some patients as a result. Higher doses of aspirin than are currently used (75-325 mg/day) may be required in these patients to achieve desired antithrombotic effects. Better understanding of aspirin-resistant populations will facilitate identification of patients who require higher aspirin doses or alternative forms of antiplatelet therapy.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Underutilization of aspirin in hemodialysis patients for primary and secondary prevention of cardiovascular disease.

BACKGROUND: Patients on hemodialysis are at high risk for cardiovascular disease (CVD). Aspirin is an established therapy for primary and secondary prevention of CVD that may be underutilized in hemodialysis patients. To better understand the use of aspirin in hemodialysis patients, we examined the experience of an urban hemodialysis center. Guidelines for use as well as associated risks and benefits are reviewed. METHODS: Medical records for patients receiving hemodialysis treatment at our center (New York City, USA) in May 2004 were reviewed for aspirin use, presence of CVD, and potential contraindications to aspirin therapy. CVD was defined as a history of coronary artery disease, ischemic stroke, transient ischemic attack, or peripheral vascular disease. Potential contraindications to aspirin therapy included history of clinically significant bleeding or increased risk of bleeding, aspirin allergy and routine treatment with other anticoagulants. RESULTS: 176 patients were eligible for the study and 172 (98%) were included. Although 74 patients had a history of CVD, only 38 (51 %) of these were treated with aspirin. Among patients with a history of CVD who were not treated with aspirin, 19 (53%) had no identifiable contraindications to aspirin therapy for secondary prevention of CVD. Ninetyeight patients had no history of CVD, and 18 (18%) of these were treated with aspirin. Of patients without a history of CVD who were not treated with aspirin, 57 (71%) had no identifiable contraindications to aspirin therapy for primary prevention of CVD. CONCLUSIONS: Aspirin is underutilized in hemodialysis patients for the primary and secondary prevention of CVD. Given the high risk of CVD in hemodialysis patients, therapy with aspirin may be of significant benefit and prospective studies of aspirin therapy are needed.

Aspirin↗
PubMed1996

Aspirin for secondary prevention after acute myocardial infarction in the elderly: prescribed use and outcomes.

OBJECTIVES: To determine how often aspirin was prescribed as a discharge medication to eligible patients 65 years of age and older who were hospitalized with an acute myocardial infarction; to identify patient characteristics associated with the decision to use aspirin; and to evaluate the association between prescription of aspirin at discharge and 6-month survival. DESIGN: Observational study. SETTING: All 352 nongovernment, acute care hospitals in Alabama, Connecticut, Iowa, and Wisconsin. PATIENTS: 5490 consecutive Medicare beneficiaries who survived an acute myocardial infarction, were hospitalized between June 1992 and February 1993, and did not have a contraindication to aspirin. MEASUREMENTS: Medical charts were reviewed to obtain information on the prescription of aspirin at discharge, contraindications, patient demographic characteristics, and clinical factors. RESULTS: 4149 patients (76%) were prescribed aspirin at hospital discharge. In a multivariable analysis, an increased prescribed use of aspirin at discharge was correlated with several indicators of better overall health status (better left ventricular ejection fraction, absence of diabetes, shorter length of hospital stay, higher albumin level, and discharge to the patient's home). The prescribed use of aspirin at discharge was also associated with several specific patterns of care, including the use of cardiac procedures, beta-blocker therapy at discharge, and aspirin during the hospitalization. The prescribed use of aspirin at discharge was associated with a lower mortality rate 6 months after discharge compared with no prescribed aspirin (odds ratio, 0.77; 95% CI, 0.61 to 0.98), even after adjustment for baseline differences in demographic, clinical, and treatment characteristics between the two groups. CONCLUSIONS: Aspirin was not prescribed at discharge to 24% of elderly patients who were hospitalized with an acute myocardial infarction and did not have a contraindication to aspirin. Several patient characteristics were associated with a higher risk for not being prescribed aspirin. Increasing the prescription of aspirin for these patients may provide an excellent opportunity to improve their care.

Aged↗
PubMed2001

Aspirin use and all-cause mortality among patients being evaluated for known or suspected coronary artery disease: A propensity analysis.

CONTEXT: Although aspirin has been shown to reduce cardiovascular morbidity and short-term mortality following acute myocardial infarction, the association between its use and long-term all-cause mortality has not been well defined. OBJECTIVES: To determine whether aspirin is associated with a mortality benefit in stable patients with known or suspected coronary disease and to identify patient characteristics that predict the maximum absolute mortality benefit from aspirin. DESIGN AND SETTING: Prospective, nonrandomized, observational cohort study conducted between 1990 and 1998 at an academic medical institution, with a median follow-up of 3.1 years. PATIENTS: Of 6174 consecutive adults undergoing stress echocardiography for evaluation of known or suspected coronary disease, 2310 (37%) were taking aspirin. Patients with significant valvular disease or documented contraindication to aspirin use, including peptic ulcer disease, renal insufficiency, and use of nonsteroidal anti-inflammatory drugs, were excluded. MAIN OUTCOME MEASURE: All-cause mortality according to aspirin use. RESULTS: During 3.1 years of follow-up, 276 patients (4.5%) died. In a simple univariable analysis, there was no association between aspirin use and mortality (4.5% vs 4.5%). However, after adjustment for age, sex, standard cardiovascular risk factors, use of other medications, coronary disease history, ejection fraction, exercise capacity, heart rate recovery, and echocardiographic ischemia, aspirin use was associated with reduced mortality (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.51-0.87; P =.002). In further analysis using matching by propensity score, 1351 patients who were taking aspirin were at lower risk for death than 1351 patients not using aspirin (4% vs 8%, respectively; HR, 0.53; 95% CI, 0.38-0.74; P =.002). After adjusting for the propensity for using aspirin, as well as other possible confounders and interactions, aspirin use remained associated with a lower risk for death (adjusted HR, 0.56; 95% CI, 0.40-0.78; P<.001). The patient characteristics associated with the most aspirin-related reductions in mortality were older age, known coronary artery disease, and impaired exercise capacity. CONCLUSION: Aspirin use among patients undergoing stress echocardiography was independently associated with reduced long-term all-cause mortality, particularly among older patients, those with known coronary artery disease, and those with impaired exercise capacity.

Aspirin↗
PubMed1983

The sex-related differences in aspirin pharmacokinetics in rabbits and man and its relationship to antiplatelet effects.

There are a number of reports which suggest that the antithrombotic effect of aspirin is limited to males. It is unclear whether this effect is due to sex-related differences in the effect of aspirin on platelets, the vessel wall, or the pharmacokinetics of aspirin. To test these possibilities we examined the sex-related differences in (1) vessel wall PGI2 release and its inhibition by and recovery from aspirin in rabbits; (2) the effects of aspirin on platelet aggregation, thromboxane B2 and beta-thromboglobulin (BTG) release in man, and (3) the pharmacokinetic characteristics of aspirin, in both rabbits and man. Vascular wall PGI2 measured as 6-keto-PGF1 alpha, was not different in male and females rabbits, and was inhibited to a similar extent by identical concentrations of aspirin. The duration of this inhibitory effect was also the same in males and females. The pattern of inhibition of collagen-induced platelet aggregation, and collagen-induced thromboxane B2 and BTG release by aspirin were not different in either sex. There was, however, a sex-related difference in a number of pharmacokinetic characteristics of aspirin both in rabbits and man. Thus, aspirin was absorbed more rapidly, distributed in larger apparent volume and was hydrolysed more rapidly in females. These observations suggest that the sex-related differences in the antithrombotic effects of aspirin seen in clinical studies are not due to differences in the effects of aspirin on the inhibition of platelet function mediated by the inhibition of cyclo-oxygenase in either the platelet or the vessel wall. An effect of aspirin on platelet function independent of the inhibition of cyclo-oxygenase has been described and it is possible that this effect may be influenced by sex-related differences in the pharmacokinetics of aspirin.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

The effect of regular and enteric-coated aspirin on bleeding time, thromboxane, and prostacyclin.

We compared the effect of different aspirin schedules, dosages, and formulations on various bleeding time parameters including bleeding time, plasma and total blood volume, and levels of the stable metabolites of thromboxane A2 (TXA2) and prostacyclin (PGI2) (respectively, TXB2 and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha)) to determine the optimal dosage and formulation of aspirin to inhibit TXA2 production while sparing PGI2. In a randomized, parallel study, 52 healthy male volunteers (62 independent observations) with no history of bleeding disorders were given 80 mg or 325 mg of regular aspirin, or 325 mg of enteric-coated aspirin to ingest daily (14 pills) or every other day (7 pills) for a continuous 14 day period. Bleeding times were performed on day 1 before aspirin, 6 h after aspirin on day 1, and before aspirin on day 14. Bleeding times, plasma volume, and total volume increased significantly from before aspirin to after 6 h and 14 days (p < 0.0001 for all parameters) for all aspirin formulations. For day 1 before aspirin ingestion to 6 h later, both TX and PGI2 (p < 0.008) decreased significantly. 6 h after ingestion of aspirin on day 1 to day 14, both TX and PGI2 levels also significantly decreased (p < 0.0001). There was a highly significant decrease in PGI2 production on every other day aspirin schedules (p = 0.0001) particularly with 80 mg of aspirin, while the decrease in PGI2 production on daily aspirin was not significant (p = 0.10). The most favourable ratio of 6-keto-PGF1 alpha to TXB2 occurred with 80 mg daily.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed2005

Aspirin sensitivity of platelet aggregation in diabetes mellitus.

Although aspirin is cardioprotective in high-risk populations, many with diabetes mellitus (DM) are unresponsive to these benefits. We questioned whether cardiovascular unresponsiveness might be demonstrated by lack of aspirin sensitivity to in vitro platelet functions especially in subjects with poorly controlled diabetes. Six women and 4 men (48+/-8 years [mean+/-S.D.]), selected for poor control (glycohemoglobin 11.9+/-2.2%) and 10 sex-age (+/-5 years) matched controls received 81 mg aspirin daily. There was a 2-week washout from aspirin and related drugs. After the aspirin dose on day-7, blood for platelet aggregation assays, and 24-h urine for 2,3 dinor thromboxane B2 (TxB2) and 2,3 dinor 6-keto (PGF1alpha) were obtained. Aspirin sensitivity was defined as inhibition (i.e., lower than expected) platelet aggregation after exposure to an agonist. Those with diabetes and controls were sensitive to aspirin inhibition of platelet aggregation induced by 1.6 mM arachidonic acid (9.5+/-3.9% versus 9.1+/-3.1%, normal range 40-100%) and by 0.83 microg/mL collagen (17.4+/-13.9% versus 13.2+/-9.3%, normal range 60-93%), respectively. Aspirin sensitivity to 2 microM ADP was present in five with diabetes and five controls. Urinary prostaglandin metabolites were suppressed below reference ranges, without differences between those with DM or controls for TxB2 (350+/-149 pg/mg versus 348+/-93 pg/mg creatinine) and PGF1alpha (255+/-104 pg/mg versus 222+/-88 pg/mg creatinine). In conclusion, in poorly controlled diabetes, there was no differential lack of aspirin sensitivity to platelet aggregation, or lack of aspirin suppression of urinary TxB2 or PGF1alpha, compared with controls on aspirin. Despite suppression of urinary prostaglandin metabolites, aspirin resistance was most apparent to ADP-mediated platelet aggregation. It is not known what level of inhibition of in vitro tests is necessary for the cardioprotective benefits of aspirin in diabetes mellitus. Thus, the lack of aspirin protection in diabetes may be due to undefined aspects of platelet function.

Aspirin↗
PubMed2005

The effect of losartan versus atenolol on cardiovascular morbidity and mortality in patients with hypertension taking aspirin: the Losartan Intervention for Endpoint Reduction in hypertension (LIFE) study.

OBJECTIVES: We conducted a subgroup analysis in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study to determine whether aspirin interacted with the properties of losartan, an angiotensin-II receptor antagonist. BACKGROUND: Negative interactions between angiotensin-converting enzyme inhibitors and aspirin have been reported. There are no data reported from clinical trials about possible interactions between angiotensin-II receptor antagonists and aspirin. METHODS: The LIFE study assigned 9,193 patients with hypertension and left ventricular hypertrophy (LVH) to losartan- or atenolol-based therapy for a mean of 4.7 years, with 1,970 (21.4%) taking aspirin at baseline. The primary composite end point (CEP) included cardiovascular death, stroke, and myocardial infarction (MI). The present cohort was stratified by aspirin use at baseline. RESULTS: Blood pressures were reduced similarly in the losartan with aspirin (n = 1,004) and atenolol with aspirin (n = 966) groups. The CEP was reduced by 32% (95% confidence interval 0.55 to 0.86, p = 0.001) with losartan with aspirin compared to atenolol with aspirin, adjusted for Framingham risk score and LVH. The test for treatment versus aspirin interaction, excluding other covariates, was significant for the CEP (p = 0.016) and MI (p = 0.037). CONCLUSIONS: There was a statistical interaction between treatment and aspirin in the LIFE study, with significantly greater reductions for the CEP and MI with losartan in patients using aspirin than in patients not using aspirin at baseline. Further studies are needed to clarify whether this represents a pharmacologic interaction or a selection by aspirin use of patients more likely to respond to losartan treatment.

Adrenergic beta-Antagonists↗
PubMed1986

A new formulation of aspirin: bioavailability and analgesic efficacy in migraine attacks.

Plasma aspirin and salicylate concentrations were followed after 600 mg of a new palatable glycinated preparation of aspirin was given to six healthy male volunteers in an attempt to investigate whether pre-gastric absorption of aspirin could occur. In each subject the drug was administered by three different routes, viz. (i) swallowed with water, (ii) dissolved sublingually and retained in the mouth, and (iii) allowed to disperse on the tongue, and then swallowed without water intake. Using the latter route of administration and the same aspirin formulation, plasma aspirin and salicylate concentrations were also followed in 10 patients during acute migraine attacks. These results were compared with those from another 10 migraineurs given 600 mg of soluble aspirin swallowed with water during attacks. Aspirin and salicylate pharmacokinetic parameters (Cmax, tmax, t1/2, Kabs and AUC) in the normal volunteers were not significantly different (p greater than 0.05) whether glycinated aspirin was swallowed with water or swallowed without water after dispersion in the mouth. However, negligible aspirin was absorbed when the glycinated preparation was retained in the mouth. In migraine patients, there was no significant difference (p greater than 0.05) between the bioavailabilities of soluble aspirin swallowed with water (AUC = 5.7 +/- 2.3 mg h/l) and glycinated aspirin swallowed without water (AUC = 4.4 +/- 1.6 mg h/l). There also was no significant difference (p greater than 0.05) when the time courses of pain relief were compared, both treatments being associated with a significant (p less than 0.01) analgesic effect. The glycinated aspirin was thus bioequivalent to swallowed aspirin but has no advantages for migraineurs over soluble aspirin if water is readily available for self-administration.

Administration, Oral↗
PubMed1991

Suppression of thromboxane A2 but not of systemic prostacyclin by controlled-release aspirin.

BACKGROUND: The antithrombotic efficacy of aspirin is attributed to its inhibition of the enzyme prostaglandin G/H synthase, which is necessary for the formation of thromboxane A2 in platelets. Thromboxane A2 is a potent vasoconstrictor and platelet agonist. However, the formation of prostacyclin by vascular endothelium also requires prostaglandin G/H synthase, and prostacyclin exerts opposite effects on platelet function and vascular tone. We wanted to see whether controlled-release aspirin would affect the formation of thromboxane A2 but not prostacyclin by reducing the aspirin concentration that reaches the posthepatic circulation. METHODS: A controlled-release formulation containing 75 mg of aspirin, designed to release 10 mg per hour, was developed to inhibit prostaglandin G/H synthase in platelets in the prehepatic circulation. The effects of the controlled-release preparation on plasma levels of aspirin and salicylate, serum levels of thromboxane B2, and urinary dinor metabolites of prostacyclin and thromboxane B2 (measured by gas chromatography-mass spectrometry) were compared with those of conventional immediate-release aspirin in normal volunteers. Prostacyclin release was stimulated by intravenous bradykinin. RESULTS: Steady-state inhibition of serum thromboxane B2 required two to four days and appeared slower with 75 mg of controlled-release than with the same amount of immediate-release aspirin. Maximal inhibition was achieved rapidly by adding a single loading dose of 162.5 mg of immediate-release aspirin to the regimen. Over a 28-day period, suppression of thromboxane A2 with this regimen was comparable to that with immediate-release aspirin taken either as 162.5 mg daily or as 325 mg on alternate days, despite the minimal systemic bioavailability of controlled-release aspirin. Bleeding time was prolonged to a similar degree with each of the three regimens. The five- to sixfold increase in the prostacyclin metabolite induced by bradykinin was depressed by pretreatment for four days with 75 mg of immediate-release aspirin, but not by 75 mg of controlled-release aspirin. CONCLUSIONS: Maximal inhibition of platelet thromboxane A2 production was sustained during long-term dosing with controlled-release aspirin, whereas basal prostacyclin biosynthesis fell only slightly and systemic synthesis of prostacyclin stimulated by bradykinin was preserved. Controlled-release aspirin may facilitate determination of the clinical importance of preserving prostacyclin during platelet inhibition in humans.

Adolescent↗
PubMed2002

Changes over time in the use of aspirin in patients hospitalized with acute myocardial infarction (1975 to 1997): a population-based perspective.

OBJECTIVE: The purpose of this study was to examine 2 decade-long trends in the use of aspirin and associated outcomes in patients hospitalized with acute myocardial infarction. BACKGROUND: Aspirin has been shown to be beneficial in the secondary prevention of AMI. However, little is known about changes over time in the use of aspirin in patients hospitalized with AMI and associated outcomes, particularly from a more generalizable population-based perspective. METHODS: We examined trends in aspirin use and hospital and long-term outcomes in 9336 metropolitan Worcester, Mass, residents hospitalized with validated AMI in all area hospitals between 1975 and 1997. RESULTS: Between 1975 and 1986, the hospital use of aspirin remained stable at approximately 20%. Use of aspirin increased markedly after this time from 49% in 1988 to 91% in 1997. Younger age, male sex, and a history of hypertension or stroke were associated with an increased likelihood of receiving aspirin. Patients with diabetes were less likely to receive aspirin than were patients without diabetes. Patients who received aspirin during hospitalization were more likely to receive beta-blockers and coronary interventions. Patients treated with aspirin were significantly less likely to have heart failure or cardiogenic shock develop or to die during hospitalization as compared with patients not treated with aspirin. Patients treated with aspirin had significantly higher survival rates over a 10-year follow-up period. CONCLUSION: The results of this community-wide study show that aspirin use in patients hospitalized with AMI has dramatically increased over time. Despite the beneficial effects associated with the use of aspirin, this therapy remains underused in several high-risk groups.

Age Distribution↗
PubMed1999

Prevention by aspirin and its combination with alpha-difluoromethylornithine of azoxymethane-induced tumors, aberrant crypt foci and prostaglandin E2 levels in rat colon.

The dose-response relationship in male F344 rats was determined for the ability of aspirin administered in the diet to prevent azoxymethane (AOM)-induced colon cancer and aberrant crypt foci (ACF) and to reduce prostaglandin E2 (PGE2) levels. Starting at either 7 or 22 weeks of age, the rats received aspirin. All rats received two doses of AOM (15 mg/kg each on days 7 and 14) and were killed on day 36. The lowest concentrations of aspirin to prevent ACF or reduce PGE2 levels were 600 and 400 mg/kg, respectively. To evaluate the prevention of tumors, rats received either 0 or 400 mg/kg aspirin for a total of 39 weeks with AOM (30 mg/kg) administered 7 days after the start of treatment. Aspirin had no effect on the yield of colon tumors. In a second experiment, rats started to receive 0, 200, 600 or 1800 mg/kg aspirin or 1000 mg/kg alpha-difluoromethylornithine (DFMO) +/- aspirin. Eight and 15 days later, all the rats received 15 mg/kg AOM. Eleven weeks later, animals that were receiving the control diet started to receive 0, 200, 600 or 1800 mg/kg aspirin; 1000 or 3000 mg/kg DFMO; or 1000 mg/kg DFMO + 200 or 600 mg/kg aspirin. The animals were killed 32 weeks later. DFMO effectively reduced the yield of colon tumors when administered starting either before or after AOM while aspirin was much weaker. The combination of aspirin + DFMO administered after AOM was synergistic. Both aspirin and DFMO decreased the Mitotic Index, while apoptosis was increased only by DFMO. Our results demonstrated that aspirin and DFMO could prevent colon cancer when administered after AOM. Furthermore, aspirin reduced ACF, PGE2 levels and mitosis at concentrations that did not prevent cancer. In contrast, the ability to enhance apoptosis did correlate with the prevention of cancer.

Animals↗
PubMed1993

Reduced risk of large-bowel adenomas among aspirin users. The Polyp Prevention Study Group.

BACKGROUND: Epidemiological studies have indicated that aspirin consumption can lower the risk of large-bowel cancer. These studies are not entirely consistent, however, and their interpretation has been complicated by the possibility that cancer symptoms may have led patients to avoid aspirin or that aspirin may have influenced cancer diagnosis and treatment. PURPOSE: Our purpose was to determine the effect of aspirin on risk of large-bowel neoplasms in a study in which aspirin use would not be expected to affect tumor detection and tumor-related symptoms would not likely influence aspirin use. A less complicated assessment of the relationship between aspirin and large-bowel tumors should thus be possible. METHODS: We studied 793 patients enrolled in a clinical trial of nutrient supplements to prevent large-bowel adenomas. Unlike invasive cancers, adenomas usually do not cause symptoms or detectable gastrointestinal bleeding; thus, adenomas are unlikely to influence aspirin use. Each patient had at least one large-bowel adenoma diagnosed and removed shortly before study entry and had been judged to be free of further tumors by colonoscopy. Use of aspirin was assessed by responses on questionnaires administered 6 and 12 months after enrollment. We performed complete colonoscopies on all patients 1 year after they entered the study and removed all polyps. RESULTS: Patients who reported taking aspirin on both questionnaires (consistent users) had a lower risk of new adenomas at their 1-year follow-up colonoscopy (odds ratio = 0.52; 95% confidence interval = 0.31-0.89) compared with patients who did not report using aspirin on either of the questionnaires. The apparent protective effect of consistent aspirin use was present among both men and women and did not appear to be influenced by the number of prior adenomas. CONCLUSIONS: These data further support the hypothesis that aspirin has an antineoplastic effect in the large bowel. Nevertheless, the question of whether aspirin should be used to prevent large-bowel tumors would be best answered by a randomized controlled clinical trial specifically designed to address this issue.

Adenoma↗
PubMed2002

Costs of aspirin and statins in general practice.

BACKGROUND: Aspirin and statins are the two drugs most commonly indicated for secondary prevention of atherosclerotic disease in the UK. Statin treatment, which is more expensive, is under-prescribed. AIM: To assess the expenditure in Greater Manchester general practices on aspirin and statins. DESIGN: Survey of general practice records. METHODS: Practice registers were searched for patients receiving regular prescriptions for aspirin. For each patient, the next patient of the same sex, aged within +/- 5 years, not on aspirin, acted as a control. Details of all medications were recorded. In a sub-study, records of 100 patients on aspirin were studied to determine indications for aspirin prescription. RESULTS: There were 1003 (511 men, 492 women) in each group; mean age was 70 years in both groups. In the sub-study, 79% of patients received aspirin for established vascular disease, 9% for hypertension, 5% for diabetes mellitus, 5% for unknown reasons and 2% for arthritis. Of the patients on aspirin, 67% received dispersible aspirin 75 mg/day. The rest were on higher doses (10%) or on more expensive preparations (22%), costing up to 22.4 p/day. The mean daily cost of aspirin was 1.7p. Dyspepsia treatment was received by 266 patients and 194 controls (p<0.001). There was a wide range of dyspepsia medications (10-306p/day), averaging in the groups as a whole 15.5p/day in patients and 12.5p/day in controls. Of the patients on aspirin, 28% received statins, compared to 4% of controls. Mean daily expenditure on statins in patients was 23.4p. CONCLUSION: Assuming the difference in the use of medication for dyspepsia between patients and controls was due to aspirin, the full cost of aspirin treatment was 4.7p/day. Statins were probably under-prescribed in aspirin-takers, many of whom would have been at high CHD risk.

Aged↗