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PubMed2000

Differential metabolism of arachidonic acid in nasal polyp epithelial cells cultured from aspirin-sensitive and aspirin-tolerant patients.

The mechanism of aspirin (acetylsalicylic acid [ASA]) sensitivity associated with severe asthma and chronic rhinosinusitis with nasal polyps ("aspirin triad") has been attributed to arachidonic metabolism alternations, although the putative biochemical defects have not been elucidated. The aim of this study was assessment of the hypothesis that local production of eicosanoids in the respiratory epithelium in patients with ASA-sensitive asthma/rhinosinusitis (ASARS) differs from that of ASA-tolerant patients with rhinosinusitis (ATRS). Nasal polyps were obtained from 10 patients with ASARS and 15 with ATRS during routine polypectomies, and epithelial cells (ECs) were cultured on bovine collagen type I matrix (Vitrogen 100), in medium supplemented with growth factors. The generation of eicosanoids in supernatants of confluent ECs (6 to 8 d of culture; purity > 98%) was quantified by immunoassays. Unstimulated ECs from ASARS patients generated significantly less prostaglandin E(2)(PGE(2)) compared with ATRS (0.8 +/- 0.3 versus 2. 4 +/- 0.5 ng/microg double-stranded deoxyribonucleic acid [dsDNA], respectively), although a similar relative increase in response to calcium ionophore and inhibition with ASA was observed in both groups. Basal levels of 15-hydroxyeicosatetraenoic acid (15-HETE) were not different between groups, and calcium ionophore enhanced its production to a similar extent. However, cells incubation with 200 microM ASA for 60 min resulted in a significant increase (mean +359%) in 15-HETE generation only in ASARS patients, whereas no effect of ASA on 15-HETE generation in ATRS patients was observed. PGF(2alpha) generation was similar in both groups, and no significant generation of PGD(2) or leukotriene C(4) (LTC(4)) was observed in epithelial cell cultures from either group. Our results indicate that nasal polyps ECs from ASA-sensitive patients have significant abnormality in basal and ASA-induced generation of eicosanoids which may be causally related to the mechanism of ASA sensitivity.

Adult↗
PubMedDate not supplied

Warfarin and aspirin versus aspirin alone in patients with acute myocardial infarction: a pilot study.

The benefits of anticoagulant therapy and antiplatelet agents in secondary prevention of myocardial infarction (MI) are well known. Administration of combined warfarin and aspirin (ASA) has not been well studied. The objective of this study was to compare the effect of coadministration of warfarin and ASA with administration of ASA alone on outcome of patients after MI. One hundred forty age- and sex-matched survivors of MI were randomized to receive either 100 mg/day ASA plus enough warfarin to reach a target: international normalized ratio of 2.5 (range: 2-3) (group A, n = 70), or only 100 mg/day ASA (group B, n = 70). The patients were examined for several variables including development of hemorrhage, reinfarction, and rehospitalization for 1 year post MI. Of the variables studied, minor hemorrhagic episodes were observed significantly (p = 0.002) more in group A than in group B patients. Rehospitalization and reinfarction rates, although occurring with lower frequencies in group A than in group B, did not reach the statistical significance level. In postmyocardial infarction patients, warfarin plus ASA did not provide a clinical benefit beyond that achievable with aspirin monotherapy, and for the observed markedly higher incidence of minor hemorrhage in combination therapy, antiplatelet therapy alone seems to be a more reasonable approach.

Adult↗
PubMed2006

Nitric oxide, aspirin-triggered lipoxins and NO-aspirin in gastric protection.

The use of nonsteroidal anti-inflammatory drugs is associated with an incidence of severe gastrointestinal adverse events of 2-4%, the most common of which is bleeding. These events are largely attributable to the ability of these drugs to suppress prostaglandin and thromboxane synthesis. Prostaglandins perform a number of important functions in the gastrointestinal tract, particularly with respect to resistance of the mucosa to injury. Nitric oxide also appears to be a key mediator of gastrointestinal mucosal defence, and this has been exploited in the development of a novel class of anti-inflammatory drugs, called "NO-NSAIDs", which exhibit little if any gastrointestinal toxicity. NO-NSAIDs are more effective than traditional NSAIDs in reducing pain and inflammation. Another class of inflammatory mediators that contribute to gastrointestinal mucosal defence are the lipoxins. These products of arachidonic acid metabolism can increase the resistance of the stomach to the damaging effects of aspirin. Indeed, aspirin can trigger the formation of a lipoxin by the stomach which acts to diminish the damaging effects of this drug. Lipoxins and nitric oxide are important mediators of mucosal defence in the stomach (and elsewhere in the gastrointestinal tract) and represent attractive therapeutic targets for reducing the incidence of gastric ulceration.

Acetylation↗
PubMed2004

Healing of chronic gastric ulcers in diabetic rats treated with native aspirin, nitric oxide (NO)-derivative of aspirin and cyclooxygenase (COX)-2 inhibitor.

Previous studies have demonstrated that the gastric mucosa of diabetic rats is highly vulnerable to acute injury but the influence of nonsteroidal anti-inflammatory drugs (NSAID) and their new nitric oxide (NO) releasing derivatives of aspirin (NO-ASA) on the ulcer healing under diabetic conditions has been little studied. In this study streptozocin (STZ, 70 mg/kg injected intraperitoneally) was used to induce diabetes mellitus in rats. Four weeks after STZ injection, gastric ulcers were induced using the acetic acid method and rats with gastric ulcers received the treatment with 1) aspirin (ASA, 30 mg/kg-d i.g.), 2) NO-ASA applied in equimolar dose of 50 mg/kg-d i.g., 3) rofecoxib (5 mg/kg-d i.g.), the selective cyclooxygenase-(COX)-2 inhibitor and 4) SNAP (5 mg/kg-d i.g.), a donor of NO, combined with ASA (30 mg/kg-d i.g.). Ten days after the induction of the ulcers, the healing rate and the gastric blood flow (GBF) were measured by planimetry and hydrogen (H(2))-gas clearance method, respectively and the plasma cytokine such as IL-1beta, TNF-alpha and IL-10 were determined. In addition, the effect of insulin (4 IU/day/rat i.p.) with or without the blockade of NO-synthase by L-NNA (20 mg/kg-d i.p.) on the ulcer healing and the GBF in non-diabetic and diabetic rats was determined. In the diabetic rats, a significant delay in ulcer healing (approximately by 300%) was observed with an accompanied decrease in the GBF at ulcer margin. The prolongation of the healing in diabetic animals was associated with an increase in the plasma cytokine (IL-1beta, TNF-alpha and IL-10) levels. ASA and rofecoxib, that significantly suppressed the mucosal prostaglandin (PG) E(2) generation in ulcer area, delayed significantly the rate of ulcer healing and decreased the GBF at ulcer margin, while elevating plasma IL-1beta, TNF-alpha and IL-10 concentrations in non-diabetic rats and these alterations were significantly augmented in diabetic animals. In contrast to ASA, the treatment with NO-ASA failed to influence both, the ulcer healing and GBF at ulcer margin and significantly attenuated the plasma levels of IL-1beta, TNF-alpha and IL-10 as compared to those recorded in ASA- or rofecoxib-treated animals. Co-treatment of SNAP with native ASA abolished the deleterious effect of ASA on ulcer healing, GBF at ulcer margin and luminal NO release in diabetic rats. Administration of insulin in rats with diabetes, opposed the delay in ulcer healing, and the fall in the GBF at ulcer margin and these effects were counteracted by the concurrent treatment with L-NNA. We conclude that: 1) ulcer healing is dramatically impaired in experimental diabetes and this effect involves the fall in the gastric microcirculation at the ulcer margin and increased release of proinflammatory cytokines; 2) classic NSAID such as ASA and selective COX-2 inhibitors such as rofecoxib, prolong ulcer healing under diabetic conditions probably due to suppression of endogenous PG and the fall in the GBF at the ulcer margin suggesting that both COX isoforms, namely, COX-1 and COX-2, are important sources of PG during ulcer healing in diabetes; and 3) NO-ASA counteracts the impairment of ulcer healing in diabetic rats induced by ASA, mainly due to the release of NO that compensates for PG deficiency resulting in enhancement in the GBF at ulcer margin and suppression of cytokine release in the ulcer area.

Animals↗
PubMed1989

Pharmacokinetics of salicylic acid following administration of aspirin tablets and three different forms of soluble aspirin in normal subjects.

The pharmacokinetic profile of an innovative formulation of soluble aspirin (l-ornithine acetylsalicylate, ldB 1003) was compared with that of conventional tablets and two other soluble dosage forms (d, l-lysine acetylsalicylate and a buffered effervescent formulation of acetylsalicylic acid) after administration of single oral doses in six normal volunteers. All soluble forms showed a rapid absorption profile, peak plasma salicylic acid levels being attained after about 30 min on average and without statistically significant differences among the solutions tested. As compared to the soluble formulations, acetylsalicylic acid given as tablets resulted in slower absorption, with peak plasma salicylic acid levels being reached more than 1 h after dosing. Despite these differences in time course of plasma level profiles, the extent of absorption was similar for all formulations. Apart from the potential advantages in terms of improved gastric tolerability, the increased rate of absorption of aspirin solutions is therapeutically useful whenever a rapid onset of action is required. In this respect, the kinetic pattern of the innovative formulation compares favourably with that of other available soluble dosage forms.

Adult↗
PubMed1985

Aspirin kinetics and inhibition of platelet thromboxane generation-relevance for a solution of the "aspirin dilemma".

Six healthy male volunteers received aspirin (ASA) in a compressed (320 mg) and an enteric-coated (800 mg) formulation as single oral doses ten days apart. Ten plasma samples were obtained from each volunteer between 5 and 120 min after compressed ASA, and seven between 10 and 240 min after enteric-coated ASA. ASA was undetectable (less than 100 ng/ml) in plasma from three subjects receiving compressed ASA and two receiving the enteric-coated preparation. Plasma levels and kinetic parameters of salicylate were the same in subjects with undetectable and detectable ASA plasma levels. More than 98% inhibition of pre-drug serum TXB2 was noted in all samples collected one and four hours after either ASA preparation. TXB2 generation recovered on average by 3.5% at 24 hr with both preparations. Thus inhibition of platelet TXB2 generation occurred independently of the amount of ASA reaching the peripheral circulation. If this is due to inhibition of platelet function in the enterohepatic circulation followed by extensive first-pass deacetylation of ASA, vascular PGI2 synthesis could be spared. A better knowledge of the kinetic parameters of ASA for each of the formulations used in thrombosis prevention trials might help in solving the "aspirin dilemma".

Adult↗
PubMed1980

Persantine-aspirin reinfarction study. Design, methods and baseline results. By the persantine-aspirin reinfarction study research group.

The Persantine-Aspirin Reinfarction Study (PARIS) was a randomized, controlled, double-blind study of dipyridamole (Persantine) and aspirin in secondary prevention of coronary heart disease. Two thousand twenty-six men and women with myocardial infarction (MI) documented by electrocardiographic findings, clinical history and cardiac enzymes were followed for a minimum of 3 years and monitored for mortality (total and cause-specific), recurrent MI and other cardiovascular events. The study had a unique structure that provides a model for large-scale industry-sponsored clinical trials. Although financed by a private pharmaceutical firm, the study was completely independent of the funding sponsor. Sixteen American and four British clinics participated in the study, along with a Coordinating Center, and ECG Reading Center, a Central Laboratory, and a Drug Distribution Center. In addition, the study included an independent Data Quality Control Center that monitored the performance of the Coordinating Center. The rationale, organization, design and baseline results are presented in this report.

Adult↗
PubMedDate not supplied

Aspirin-induced neutrophil chemotactic activity (NCA) in patients with aspirin-sensitive urticaria after desensitization to the drug.

The increase in neutrophil chemotactic activity (NCA) is related to mast cell degranulation. This study was performed in 10 patients in whom aspirin-induced urticaria was connected with increased NCA. A state of tolerance to aspirin (ASA) was achieved by administering incremental doses of acetylsalicylic acid. In none of the examined patients was an increase in NCA observed after 600 mg of ASA given after desensitization. The authors conclude that in patients with ASA-induced urticaria, mast cell degranulation does not occur after ASA desensitization.

Adult↗
PubMed1993

The leukotriene-receptor antagonist MK-0679 blocks airway obstruction induced by inhaled lysine-aspirin in aspirin-sensitive asthmatics.

Drugs which block the action or formation of the cysteinyl leukotrienes (LTC4, LTD4 and LTE4) inhibit asthmatic responses evoked by allergen, exercise and cold dry air. The purpose of this study was to determine whether the specific leukotriene-receptor antagonist MK-0679 could block the airway obstruction induced by aspirin (acetylsalicylic acid (ASA)) in aspirin-intolerant asthmatics. Eight asthmatics (mean age 45 yrs), with an average history of asthma and ASA-sensitivity of about 10 yrs duration, were subjected to bronchial provocation with lysine-ASA. Baseline ASA-sensitivity was first determined in an open prestudy session by inhalation of cumulative doses of lysine-ASA to establish the dose of ASA decreasing forced expiratory volume in one second (FEV1) by 20% (PD20). Rechallenge with lysine-ASA was performed on two different occasions, 1 h after oral administration of placebo, or 750 mg of MK-0679, under double-blind conditions, in a randomized, cross-over design. Leukotriene formation was estimated by the measurement of urinary LTE4. The lysine-ASA challenge was highly reproducible (geometric mean for group PD20 being identical for the open prestudy and the placebo session), and was associated with a post-challenge increase in urinary LTE4. In contrast, after MK-0679, there was a rightward shift in the dose response relationship for all eight subjects (median shift being 4.4 fold), with three of the subjects failing to produce a 20% decrease in FEV1 despite inhalation of the highest dose of lysine-ASA feasible to deliver.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspirin↗
PubMed1980

Aspirin--a national survey IV: In vitro dissolution of aspirin formulations.

The results of a national survey of the in vitro dissolution rates of aspirin tablets are presented. Dissolution profiles by both the proposed USP XX basket method and a paddle method are compared. The methods were used to analyze 59 tablet formulations representing 38 manufacturers. Each tablet was subjected to the dissolution procedure in 500 ml of pH 4.5 buffer solution, and an aliquot was sampled automatically and analyzed by an automated system. In 30 min, 22% of the samples tested using the basket method failed the proposed USP XX dissolution requirement. Seventy-five percent of the samples tested By the paddle method also failed the proposed dissolution requirement.

Alcohols↗
PubMed1990

Long-term effects of aspirin desensitization--treatment for aspirin-sensitive rhinosinusitis-asthma.

One hundred seven known aspirin (ASA)-sensitive patients with rhinosinusitis-asthma were studied from 1975 to 1988. Forty-two of the patients avoided ASA and served as the control group. Thirty-five patients were desensitized to ASA and treated with daily ASA treatment (Rx) for as long as 8 years (mean, 3.75 years) to May 1988 and were designated the continuous group. Thirty patients, initially desensitized to ASA and treated with daily ASA, who stopped Rx permanently after a mean duration of 2 years, were designated the discontinued group. Retrospective analyses of baselines revealed that both continuous and discontinued groups during ASA Rx demonstrated statistically significant reduction in number of hospitalizations per year, emergency room visits per year, outpatient visits per year, upper respiratory infections-sinusitis-antibiotics per year, need for nasal polypectomies and additional sinus operations, and improvement in sense of smell compared to the control group. Simultaneously, the ASA-Rx groups were able to significantly reduce systemic corticosteroid dosage, corticosteroid bursts per year, and, in the continuous group only, significantly reduce inhaled corticosteroids. All three groups maintained control of respiratory symptoms. ASA desensitization followed by long-term daily ASA Rx appears to improve ASA-sensitive rhinosinusitis-asthma and concomitantly allows reduction of systemic corticosteroids.

Adrenal Cortex Hormones↗
PubMed2005

Influence of aspirin resistance on platelet function profiles in patients on long-term aspirin and clopidogrel after percutaneous coronary intervention.

Increased platelet inhibition is achieved when clopidogrel is added to aspirin (acetylsalicylic acid [ASA]). A broad variability in platelet inhibition profiles during the early phases of treatment has been demonstrated and may be attributed to ASA resistance. However, the influence of ASA sensitivity on platelet function profiles of patients on long-term dual antiplatelet therapy has yet to be explored. A total of 135 patients who had previously undergone percutaneous coronary intervention on long-term (>1 month) ASA and clopidogrel therapy was included. The PFA-100 system was used to define ASA resistance. Platelet aggregation, after adenosine diphosphate (6 and 20 micromol/L) and collagen (6 microg/ml) stimuli, and platelet activation (glycoprotein IIb/IIIa activation and P-selectin expression), after adenosine diphosphate (2 micromol/L) and thrombin receptor-activating peptide (50 micromol/L) stimuli, were assessed by light transmittance aggregometry and flow cytometry, respectively. Patient variability in response to treatment was defined by the coefficient of variability. ASA resistance was found in 60 of 135 patients (44%). Patients with diabetes were more frequently ASA resistant. Collagen/epinephrine- and collagen/adenosine diphosphate-coated cartridges on the PFA-100 had shorter closure times in the ASA-resistant population compared with ASA-sensitive patients. Platelet aggregation and activation were significantly higher in ASA-resistant patients. A broad variability (coefficient of variation >0.25) in patient response to treatment was observed in ASA-resistant and -sensitive patients. In conclusion, ASA resistance is associated with increased platelet reactivity in patients on long-term dual antiplatelet treatment.

Adenosine Diphosphate↗
PubMed1976

Application of gas-liquid chromatography and high-performance liquid chromatography to the analysis of trace amounts of salicylic acid, acetylsalicylic anhydride and acetylsalicylsalicylic acid in aspirin samples and aspirin formulations.

The gas-liquid chromatographic (GLC) determination of salicylic acid (SA) in 12 commercial acetylsalicylic acid (aspirin, ASA) samples and 12 ASA formulations is reported. The GLC determination of SA as an impurity in ASA, utilising methylation with methyl iodide in the presence of potassium carbonate, requires a column chromatographic separation of SA prior to derivatization. Trace amounts of SA in ASA have also been determined by high-performance liquid chromatography (HPLC) on a Sil-X-I adsorption column using light petroleum-ethyl acetate-acetic acid as the mobile phase. Acetylsalicylic anhydride (ASN) and acetylsalicylsalicylic acid (ASSA) were determined by HPLC on a reversed-phase C18 column with water-methanol mixtures as the mobile phase. GLC was also applied to the determination of ASN as an impurity in ASA formulations.

Anhydrides↗
PubMed2000

Aspirin plus extended-release dipyridamole or clopidogrel compared with aspirin monotherapy for the prevention of recurrent ischemic stroke: a cost-effectiveness analysis.

OBJECTIVE: The goal of this health economic analysis was to asses the cost-effectiveness of a fixed combination of aspirin plus extended-release dipyridamole (ASA/ER-DP) or clopidogrel compared with ASA monotherapy for prevention of recurrent ischemic stroke. BACKGROUND: The second European Stroke Prevention Study (ASA/ESPS-2), a large-scale clinical trial, demonstrated that a new therapy--a fixed combination of ASA/ER-DP--is more effective than ASA monotherapy for the prevention of recurrent ischemic stroke. METHODS: We used data from ESPS-2 to create a health economic model that estimates the incremental cost and cost-effectiveness of ASA/ER-DP during the 2-year time frame after an ischemic stroke. The model was developed from a payor perspective. The analysis used direct cost estimates for stroke from a Medicare claims database analysis. Efficacy data were obtained from clinical trials to determine the incremental cost per stroke averted for ASA/ER-DP or clopidogrel versus ASA. Sensitivity analyses also were conducted to test the reliability and robustness of the model. RESULTS: The results of the analysis demonstrated that ASA/ER-DP was cost-effective compared with ASA monotherapy for the secondary prevention of stroke, with a cost-effectiveness ratio of $28,472. The model remained robust over a range of assumptions and cost estimates. Clopidogrel, however, was not cost-effective compared with ASA (cost per stroke averted, $161,316) in either the base-case analysis or any of the sensitivity analyses. CONCLUSION: ASA/ER-DP thus offers a cost-effective alternative to ASA monotherapy for the prevention of recurrent ischemic stroke.

Aspirin↗
PubMed2003

A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary artery stents.

OBJECTIVES: The aim of the present study was to compare clopidogrel and ticlopidine after coronary stenting with regard to cardiovascular death during long-term follow-up. BACKGROUND: Randomized trials comparing clopidogrel and ticlopidine with a restricted use of intravenous glycoprotein IIb/IIIa inhibition have reported a trend toward a higher incidence of thrombotic stent occlusion with clopidogrel at 30 days. METHODS: After successful coronary stent implantation, 700 patients with 899 lesions were randomly assigned to receive a four-week course of either 500 mg ticlopidine (n = 345) or 75 mg clopidogrel (n = 355) in addition to 100 mg aspirin. Cardiovascular death was the primary end point and was recorded during a median follow-up period of 28 months. RESULTS: Cardiovascular death occurred in eight patients with ticlopidine versus 26 patients with clopidogrel (hazard ratio with ticlopidine compared with clopidogrel, 0.30; 95% confidence interval [CI], 0.14 to 0.66; p = 0.003). After adjustment for co-variables, ticlopidine reduced the risk of cardiovascular death by 63% compared with clopidogrel. The combined end point of cardiovascular death or nonfatal myocardial infarction was present in 19 patients assigned ticlopidine, compared with 40 patients assigned clopidogrel (hazard ratio, 0.45; p = 0.005). The hazard ratio for all-cause mortality with ticlopidine as compared with clopidogrel was 0.30 (95% CI, 0.14 to 0.64; p = 0.002). CONCLUSIONS: After the placement of coronary artery stents in unselected patients, ticlopidine was associated with a significantly lower mortality than clopidogrel. This raises concern about the current practice of substituting clopidogrel for ticlopidine after stenting and highlights the need for further long-term studies.

Aged↗
PubMed2003

Early effects of aspirin desensitization treatment in asthmatic patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin (ASA)-exacerbated respiratory disease (AERD) is characterized by aggressive inflammation of the respiratory tract and often requires topical and/or systemic corticosteroids to maintain partial control of this disease. Previous studies have revealed that ASA desensitization and subsequent treatment with ASA is associated with clinical improvement in AERD. OBJECTIVE: The aim of the present study was to determine the effect of daily ASA treatment for the first 4 weeks after ASA desensitization. METHODS: Thirty-eight patients underwent ASA oral challenge followed by ASA desensitization and daily ASA therapy. Changes in nasal and asthma symptoms, combined with changes in oral prednisone, were recorded daily during 4 weeks before and after desensitization. Severity of symptoms ranged from a scale of 1 to 5 (1 = asymptomatic and 5 = most severe symptoms). For statistical analyses the sum of nasal symptoms and asthma symptoms was calculated. Olfactory scores were also analyzed. RESULTS: Nasal and asthma symptom scores, as well as olfactory scores, improved significantly (P < 0.0001). For the 15 patients taking prednisone, their mean doses decreased from 10.7 to 5.9 mg daily (P = 0.0003). CONCLUSIONS: Our study suggests that ASA desensitization treatment is effective during the first 4 weeks of daily treatment with ASA.

Adult↗
PubMed2006

Prophylaxis of recurrent preeclampsia: low-molecular-weight heparin plus low-dose aspirin versus low-dose aspirin alone.

OBJECTIVE: To verify whether prophylaxis with low-molecular-weight heparin (LMWH) and low-dose aspirin (LDA) could positively affect pregnancy outcome in women with a history of severe preeclampsia. METHODS: We compared 23 pregnancies treated with LDA alone to 31 pregnancies treated with LMWH plus LDA. RESULTS: Women treated with LMWH-LDA (n = 31) showed a better pregnancy outcome than those treated with LDA alone (n = 23) in terms of gestational age at delivery (p < 0.05), birth weight (p < 0.01), birth weight percentile (p < 0.01), and rate of preeclampsia (p < 0.01). Furthermore, comparing the intra-group outcome variation between previous and index pregnancies, an improvement appeared in each group, but a more pronounced gain was noted in the LMWH-LDA group in terms of gestational age at delivery (p< 0.005), birth weight (p < 0.005), and birth weight percentile (p < 0.005). CONCLUSIONS: Thromboprophylaxis with LMWH plus LDA can improve pregnancy outcome in women with previous severe preeclampsia.

Adult↗
PubMed2006

Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin.

AIMS: This double-blind, parallel-group study was conducted to assess the pharmacodynamics, pharmacokinetics, and safety of AZD6140, the first oral, reversible adenosine diphosphate (ADP) receptor antagonist. METHODS AND RESULTS: Patients (n = 200) with atherosclerosis were randomized to receive AZD6140 50, 100, or 200 mg twice daily (bid) or 400 mg daily (qd) or clopidogrel 75 mg qd for 28 days. All groups received aspirin 75-100 mg qd. AZD6140 (100 and 200 mg bid, 400 mg qd) rapidly and nearly completely inhibited ADP-induced platelet aggregation after initial dosing (day 1) and at day 28. On day 1, peak final-extent inhibition of platelet aggregation (IPA) was observed 2-4 h post-dose with AZD6140, whereas clopidogrel minimally inhibited platelet aggregation (mean percentage IPA < 20%, all time points). Four hour post-dose at steady state, the three higher doses of AZD6140 produced comparable final-extent mean percentage IPA (approximately 90-95%), which exceeded that with AZD6140 50 mg bid or clopidogrel (approximately 60%). AZD6140 was generally well tolerated. All bleeding events, except one in a patient receiving 400 mg qd, were minor and of mild-to-moderate severity. CONCLUSION: AZD6140 100 and 200 mg bid were well tolerated and were superior to AZD6140 50 mg bid and clopidogrel 75 mg qd with regard to antiplatelet efficacy.

Adenosine↗