Aspirin In Healthy Volunteers Research Articles

Aspirin-Dependent Effects on Purinergic P2Y1 Receptor Expression.

Chronic treatment with aspirin in healthy volunteers (HVs) is associated with recovery of adenosine diphosphate (ADP)-induced platelet activation. The purinergic P2Y1 receptor exerts its effects via a Gq-protein, which is the same biochemical pathway activated by thromboxane-A2 receptor. We hypothesized that recovery of ADP-induced platelet activation could be attributed to increased P2Y1 expression induced by chronic aspirin exposure. We performed a multi-phase investigation which embraced both in vitro and in vivo experiments conducted in (1) human megakaryoblastic DAMI cells, (2) human megakaryocytic progenitor cell cultures, (3) platelets obtained from HVs treated with aspirin and (4) platelets obtained from aspirin-treated patients. DAMI cells treated with aspirin or WY14643 (PPARα agonist) had a significant up-regulation of P2Y1 mRNA, which was shown to be a PPARα-dependent process. In human megakaryocytic progenitors, in the presence of aspirin or WY14643, P2Y1 mRNA expression was higher than in mock culture. P2Y1 expression increased in platelets obtained from HVs treated with aspirin for 8 weeks. Platelets obtained from patients who were on aspirin for more than 2 months had increased P2Y1 expression and ADP-induced aggregation compared with patients on aspirin treatment for less than a month. Overall, our results suggest that aspirin induces genomic changes in megakaryocytes leading to P2Y1 up-regulation and that PPARα is the nuclear receptor involved in this regulation. Since P2Y1 is coupled to the same Gq-protein of thromboxane-A2 receptor, platelet adaptation in response to pharmacological inhibition seems not to be receptor specific, but may involve other receptors with the same biochemical pathway.

Over-expression of cyclooxygenase-2 in increased reticulated platelets leads to aspirin resistance after elective off-pump coronary artery bypass surgery

IntroductionAspirin resistance (AR) has been reported to present after coronary artery bypass graft causing saphenous vein graft failure. We aimed to investigate the factors that affect the anti-platelet effect of aspirin after off-pump coronary artery bypass surgery (OPCAB). Materials and methodsThirty OPCAB candidates were successively recruited. Platelet count, platelet aggregation, reticulated platelet (RP), platelets' cyclooxygenase (COX)-1 and COX-2 expressions were determined during the peri-operative period. Besides, 10 healthy volunteers were enrolled to determine the onset of the anti-platelet effect of aspirin as comparison. Results and conclusionsThe arachidonic acid-induced platelet aggregation (PLAA) decreased to <20% within 8h after taking 100mg aspirin in healthy volunteers. However, in the OPCAB patients, PLAA levels remained over 20% in 16 (53.3%) patients after resuming aspirin for 24h. The surgical bleeding volumes were higher in the AR patients compared to the normal responders (512.5±192.8 vs. 314.3±94.9, p=0.002). The platelet count on Day 8, RP proportions on Days 1, 4, 8, and COX-2 level on Day 4 were significantly increased compared to their baseline levels in AR group but not in AS group. Platelet count on Day 8, RP proportion and COX-2 on Day 4 were all significantly higher in AR group than those in AS group. The surgical bleeding volume and COX-2 over-expression were predictors of post-OPCAB AR. As a conclusion, the inability of aspirin to inhibit the COX-2 created by increased RP would account for the post-OPCAB AR.

Comparison of antiplatelet activity of garlic tablets with cardio-protective dose of aspirin in healthy volunteers: a randomized clinical trial.

Some of the adverse effects of aspirin including peptic ulcers, gastrointestinal bleeding and aspirin resistance compelled researchers to find a suitable alternative with fewer adverse effects. In this clinical trial, we aimed to find the effective antiplatelet dose of garlic. This randomized controlled clinical trial (RCT) was conducted on 62 healthy volunteers of 20-50 years old. All volunteers used 80 mg aspirin per day for 1 week and at the end of this time, platelet aggregation (PA) induced by 4 agonists acting in aggregation pathway including adenosinediphosphate (20 μmol/l), epinephrine (20 μmol/l), collagen(0.19 mg/ ml) and arachidonic acid (0.5mg/ ml) was measured by Light Transmittance Aggregometry (LTA) in all participants. After one month washout period, volunteers were randomized into 3 groups and each received 1, 2 or 3 garlic tablets (1250 mg) a day for 1 month. After one month, PA was examined in all groups. The mean ±SD of the age of all volunteers was 28.60 ± 9.00 years. In addition, 52.00 % of our volunteers were male and 48.00% of them were female. Garlic tablet didnot have significant effect on PA at any dose. However, 30% of volunteers in the group that used 3 garlic tablets/day reported adverse effect (i.e. bleeding). No significant association between sex, age and PA was observed. In this study, we were unable to determine the effective anti-platelet dose of garlic which that could be equal to that of aspirin anti-platelet activity, as assessed LTA method.

Comparison of aspirin and indobufen in healthy volunteers

The aim of this study is to quantify the extent and recovery of platelet inhibition after administration of indobufen and aspirin in healthy volunteers. Indobufen inhibits platelet aggregation by reversibly inhibiting the platelet cyclooxygenase enzyme, thereby suppressing thromboxane synthesis. Twenty healthy volunteers completed the study and received aspirin (200 mg/day for 2 weeks) followed by a 4-week washout period and then indobufen (200 mg twice a day for 2 weeks). The percent (%) inhibition of platelet aggregation (IPA) was assessed using arachidonic acid (0.5 mg/ml) and adenosine diphosphate (5 µM) at 4, 12, 24 and 48 hours after last dose of each drug. IPA assessed using arachidonic acid as the agonist was similar at 4 hours after the last dose of indobufen (81.07 ± 9.36%) and aspirin (96.99 ± 0.29%, p = 0.10), but significantly lower at 12 hours (74.04 ± 9.55% vs. 97.94 ± 0.28%, p = 0.02), 24 hours (33.39 ± 11.13% vs. 97.48 ± 0.32%, p < 0.001) and 48 hours (14.12 ± 9.74% vs. 98.22 ± 0.31%, p < 0.001) after indobufen, compared to the relative values for aspirin. IPA assessed using adenosine diphosphate as the agonist was similar in the two groups at 4, 12 and 24 hours after the last dose, but significantly lower 48 hours after the last dose of indobufen, compared to the relative value for aspirin (1.98 ± 3.57% vs. 12.61 ± 2.71%, p = 0.002). Indobufen (200 mg twice a day) caused equivalent initial inhibition of platelet aggregation to aspirin (200 mg daily), and the anti-aggregation effect diminished faster than after aspirin.

Pharmacokinetic Evaluation of Administration of Losartan with Aspirin in Healthy Volunteers

Losartan and aspirin are often used concomitantly in patients with heart failure, ischemic heart disease and hypertension. Objectives: To investigate whether aspirin co-administration affects losartan bioavailability. Methods: 1) Twenty-four healthy volunteers from both sexes were recruited. Volunteers received a single 50 mg losartan with or without a 81 mg aspirin tablet. Blood samples were obtained at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.33, 2.67, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12 hour post-dosing. The concentrations of losartan were analyzed by LC-MSMS. Clearance (Cl) and T1/2 were used to evaluate a possible drug-drug interaction. Cmax and AUC0-8 were used to evaluate whether co-administration interferes on the bioavailability process. Results: From the losartan plasma concentrations vs. time curves the following pharmacokinetic parameters were obtained: ASC0-8 hours, AUCinf, Cmax, Cl, Vd, Tmax, Ke and T1/2. No significant differences were observed in T1/2 (p-value = 0.431), Cl (p-value = 0.554), AUC0-8 hours (p-value = 0.590), Cmax (p-value = 0.987) and Vd (p-value = 0.647). Conclusions: Since there is no significant difference in losartan bioavailability and elimination when coadministered with aspirin, we conclude that there is no pharmacokinetic interaction between both drugs. The finding is important since it reassures the safe use of combining AAS to losartan treatment.

12-hydroxyeicosatetraenoic acid is associated with variability in aspirin-induced platelet inhibition.

BackgroundAspirin is one of the most widely used non-steroidal anti-inflammatory drugs (NSAIDs). It is also a commonly used anti-platelet drug, which inhibits the formation of the platelet activator, thromboxane A2 (TxA2) via inhibition of cyclooxygenase-1 (COX-1). However, the presence of a patient subset that fails to respond to aspirin despite reduced TxA2 concentrations suggests that the effect of aspirin might be more complex than exclusive COX-1 inhibition.MethodsIn this study we evaluated the impact of in vivo oral administration of a standard anti-platelet dose (75 mg) of aspirin in healthy volunteers on the acute impact of in vitro collagen-mediated platelet aggregation and generation of platelet-derived TxA2 and the 12-lipoxygenase (LOX) metabolite 12-hydroxyeicosatetraenoic acid (12-HETE). The eicosanoids were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS).ResultsLow-dose aspirin administration not only inhibited TxA2 generation but also decreased the production of 12-HETE. Furthermore, a significant correlation was observed between the levels of 12-HETE and collagen-induced platelet aggregation. Pre-treatment of platelets with the 12-LOX inhibitor, baicalein, prior to activation attenuated platelet aggregation.ConclusionsThese findings support a role for 12-HETE as a pro-aggregatory eicosanoid in platelet function and suggest a role for 12-HETE in variable sensitivity to aspirin. The study also highlights a potentially important mechanism by which aspirin impacts upon eicosanoid generation.

Gastrointestinal symptoms in low-dose aspirin users: a comparison between plain and buffered aspirin

BackgroundAspirin is associated with gastrointestinal side effects such as gastric ulcers, gastric bleeding and dyspepsia. High-dose effervescent calcium carbasalate (ECC), a buffered formulation of aspirin, is associated with reduced gastric toxicity compared with plain aspirin in healthy volunteers, but at lower cardiovascular doses no beneficial effects were observed.AimTo compare the prevalence of self-reported gastrointestinal symptoms between low-dose plain aspirin and ECC.MethodsA total of 51,869 questionnaires were sent to a representative sample of the Dutch adult general population in December 2008. Questions about demographics, gastrointestinal symptoms in general and specific symptoms, comorbidity, and medication use including bioequivalent doses of ECC (100 mg) and plain aspirin (80 mg) were stated. We investigated the prevalence of self-reported gastrointestinal symptoms on ECC compared with plain aspirin using univariate and multivariate logistic regression analyses.ResultsA total of 16,715 questionnaires (32 %) were returned and eligible for analysis. Of these, 911 (5 %) respondents reported the use of plain aspirin, 633 (4 %) ECC and 15,171 reported using neither form of aspirin (91 %). The prevalence of self-reported gastrointestinal symptoms in general was higher in respondents using ECC (27.5 %) compared with plain aspirin (26.3 %), but did not differ significantly with either univariate (OR 1.06, 95 %CI 0.84–1.33), or multivariate analysis (aOR 1.08, 95 %CI 0.83–1.41). Also, none of the specific types of symptoms differed between the two aspirin formulations.ConclusionsIn this large cohort representative of the general Dutch population, low-dose ECC is not associated with a reduction in self-reported gastrointestinal symptoms compared with plain aspirin.Electronic supplementary materialThe online version of this article (doi:10.1007/s12471-014-0522-3) contains supplementary material, which is available to authorized users.

Tolerability and Pharmacokinetics of Delayed-Release Dimethyl Fumarate Administered With and Without Aspirin in Healthy Volunteers

BackgroundDelayed-release dimethyl fumarate (DR-DMF) has cytoprotective and antiinflammatory properties and has recently been approved in the United States as an oral treatment for relapsing forms of multiple sclerosis. The most common adverse events associated with DR-DMF are flushing and gastrointestinal (GI) events, the incidences of which diminish over time. ObjectiveThe purpose of this study was to evaluate the tolerability and pharmacokinetic (PK) profile of DR-DMF with or without concomitant acetylsalicylic acid (aspirin), a cyclooxygenase inhibitor. MethodsHealthy volunteers (N = 56) were randomized to receive different dosing regimens of DR-DMF or matching placebo with or without pretreatment with 325 mg aspirin for 4 days. Plasma levels of the active metabolite monomethyl fumarate were assessed on days 1 and 4. Flushing and GI events were assessed using patient-reported scales. Potential flushing mediators were explored. ResultsDR-DMF showed a safety, tolerability, and PK profile consistent with previous clinical experience, with no evidence of accumulation. Pretreatment with aspirin had no effect on the primary PK parameters, AUC0–10h, or Cmax. Flushing severity, assessed by 2 subject-reported rating scales, was generally mild and was rated highest at the start of treatment. Pretreatment with aspirin reduced flushing incidence and intensity without affecting GI events or the PK profile of DR-DMF. In some DR-DMF–treated individuals, plasma concentrations of a prostaglandin D2 (PGD2) metabolite were increased. ConclusionsIn healthy volunteers, DR-DMF was well tolerated over 4 days of dosing, with a PK profile consistent with that previously reported and no evidence of accumulation. Aspirin pretreatment reduced the incidence and intensity of flushing without affecting GI events or the DR-DMF PK profile. Elevated levels of PGD2 in some DR-DMF–treated individuals suggest that flushing may be, at least in part, prostaglandin mediated. ClinicalTrials.gov identifier: ID: NCT01281111.

Evaluation of the pharmacokinetics and pharmacodynamics of ticagrelor co-administered with aspirin in healthy volunteers

The results of two independent, randomized, two-period crossover, single-center studies, conducted to assess the pharmacokinetics of ticagrelor ± aspirin, inhibition of platelet aggregation (IPA) with ticagrelor/aspirin vs. clopidogrel/aspirin, and safety, tolerability, and bleeding times are reported here. In Study A (open-label), 16 volunteers received ticagrelor (50 mg bid Days 1–5; 200 mg bid Days 6–9; one 200 mg dose on Day 10) ± 300 mg qd aspirin (Days 1–10). In Study B (double-blind, double-dummy), 16 volunteers received aspirin (300 mg loading dose/75 mg qd Days 2–9) with either ticagrelor (200 mg bid Days 4–8, one 200 mg dose on Day 9) or clopidogrel (300 mg loading dose Day 4, 75 mg qd Days 5–9). At steady-state ticagrelor (50 mg bid, or 200 mg bid), concomitant aspirin (300 mg qd) had no effect on mean maximum plasma concentration (Cmax), median time to Cmax (tmax), or mean area under the plasma concentration-time curve for the dosing interval (AUC0–τ) for ticagrelor and its primary metabolite, AR-C124910XX. Following 200 mg bid ticagrelor, mean Cmax and AUC0–τ for both parent and metabolite were comparable with co-administration of aspirin at 75 mg and 300 mg qd. Aspirin (300 mg qd) had no effect on IPA (ADP-induced) by ticagrelor. However, aspirin and ticagrelor had an additive effect on IPA (collagen-induced). Ticagrelor/aspirin increased bleeding times vs. baseline. Ticagrelor/aspirin co-administration was well tolerated at all dose combinations evaluated. In summary, the findings of this study demonstrate that co-administration of aspirin (300 mg qd) with ticagrelor (50 mg bid, or 200 mg bid) had no effect on ticagrelor pharmacokinetics or IPA (ADP-induced) by ticagrelor.

Time-dependent changes in non-COX-1-dependent platelet function with daily aspirin therapy

To develop an integrated metric of non-COX-1-dependent platelet function (NCDPF) to measure the temporal response to aspirin in healthy volunteers and diabetics. NCDPF on aspirin demonstrates wide variability, despite suppression of COX-1. Although a variety of NCDPF assays are available, no standard exists and their reproducibility is not established. We administered 325 mg/day aspirin to two cohorts of volunteers (HV1, n = 52, and HV2, n = 96) and diabetics (DM, n = 74) and measured NCDPF using epinephrine, collagen, and ADP aggregometry and PFA100 (collagen/epi) before (Pre), after one dose (Post), and after several weeks (Final). COX-1 activity was assessed with arachidonic acid aggregometry (AAA). The primary outcome of the study, the platelet function score (PFS), was derived from a principal components analysis of NCDPF measures. The PFS strongly correlated with each measure of NCDPF in each cohort. After 2 or 4 weeks of daily aspirin the Final PFS strongly correlated (r > 0.7, P < 0.0001) and was higher (P < 0.01) than the Post PFS. The magnitude and direction of the change in PFS (Final–Post) in an individual subject was moderately inversely proportional to the Post PFS in HV1 (r = -0.45), HV2 (r = -0.54), DM (r = -0.68), P < 0.0001 for all. AAA remained suppressed during aspirin therapy. The PFS summarizes multiple measures of NCDPF. Despite suppression of COX-1 activity, NCDPF during aspirin therapy is predictably dynamic: those with heightened NCDPF continue to decline whereas those with low/normal NCDPF return to pre-aspirin levels over time.

Effects of different doses, enteric-coated preparation of aspirin, and sex on urinary 11-dehydrothromboxane B2 in healthy volunteers

There is scarce information about the effects of different doses and enteric-coated preparation of aspirin on platelet function, especially in Asian people, evaluated by the measurement of urinary 11-dehydrothromboxane B2 (dTXB2). The objective of the present study was to assess the effects of different doses, enteric-coated preparation of aspirin, sex and also the effects of timing of urine collection on urinary dTXB2 level in healthy volunteers. Thirty healthy volunteers were included. Each volunteer took three preparations of aspirin (aspirin 81 mg, enteric-coated aspirin 300 mg and aspirin 300 mg) for 7 days. Urine dTXB2 level was measured at baseline, day 3, and day 7 after taking each preparation of aspirin. There was no significant difference in the effects of different doses of aspirin (81 vs. 300 mg, 50.7 vs. 61.8 ng/mmol creatinine, P = 0.248), preparations (enteric-coated vs. nonenteric-coated aspirin, 61.8 vs. 67.9 ng/mmol creatinine, P = 0.527) and time of urine collection (day 3 vs. day 7, 51.7 vs. 49.9 ng/mmol creatinine, P = 0.448). Female volunteers showed a trend to have higher urinary dTXB2 than male volunteers at baseline and after taking aspirin. This study showed no significant difference in urinary dTXB2 level after taking different doses and enteric-coated preparation of aspirin in healthy volunteers.

The interaction of ibuprofen and diclofenac with aspirin in healthy volunteers

Aspirin reduces the risk of myocardial infarction and stroke by inhibiting thromboxane production in platelets. This inhibition can be competitively antagonized by some non-steroidal anti-inflammatory drugs (NSAIDs). By measuring thromboxane B(2) production in healthy volunteers, we investigated whether ibuprofen (800 mg three times daily for 7 days) or diclofenac (50 mg three times daily for 7 days) taken concurrently with aspirin 80 mg (once daily for 7 days) influenced the inhibitory effect of aspirin. The effects were compared with aspirin 30 mg (once daily for 7 days), which is the lowest dose of aspirin with a proven thromboprophylactic effect. The median percentage inhibition of thromboxane B(2) levels by 30 mg or 80 mg aspirin was 90.3% (range 83.1-96.0%) and 98.0% (range 96.8-99.2%) respectively. The inhibition by concurrent administration of slow release diclofenac and 80 mg aspirin was 98.1% (range 97.2-98.9%), indicating no interference between aspirin and diclofenac. The inhibition decreased significantly by concurrent administration of immediate release ibuprofen and 80 mg aspirin (86.6%; range 77.6-95.1%) to a level less than 30 mg aspirin. As alternatives are easily available, NSAIDs such as diclofenac should be preferred to ibuprofen for combined use with aspirin.

W1920 Study of Relationship Between Intragastric pH and Gastric Mucosal Lesions Induced By Low-Dose Aspirin in Healthy Volunteers

W1920 Study of Relationship Between Intragastric pH and Gastric Mucosal Lesions Induced By Low-Dose Aspirin in Healthy Volunteers

The Antiplatelet Effect of Six Non-Steroidal Anti-Inflammatory Drugs and Their Pharmacodynamic Interaction With Aspirin in Healthy Volunteers

Patients with cardiovascular disease taking aspirin and some nonsteroidal anti-inflammatory drugs (NSAIDs) appear to have increased vascular events. This study was conducted to compare the ex vivo antiplatelet effects of 6 commonly used NSAIDs and to determine whether these agents antagonize the effect of aspirin. Platelet function was assessed by Platelet Function Analyzer 100 closure time in normal subjects in a randomized, blinded, multiple-crossover study. Platelet function was measured 12 hours after the administration of each NSAID. The NSAID was then given 2 hours before aspirin 300 mg, and platelet function was reassessed 24 hours later. At 12 hours after the administration of naproxen and tiaprofenic acid, closure time was significantly prolonged, whereas the other NSAIDs did not cause significant prolongations. Compared with placebo plus aspirin, closure time was significantly reduced when ibuprofen, indomethacin, naproxen, or tiaprofenic acid was given before aspirin. In conclusion, ibuprofen, indomethacin, naproxen, and tiaprofenic acid all block the antiplatelet effect of aspirin. Sulindac and celecoxib did not demonstrate any significant antiplatelet effect or reduce the antiplatelet of aspirin and, therefore, of the NSAIDs evaluated may be the drugs of choice for patients requiring aspirin and NSAIDs.

Effect of Ranitidine on the Antiplatelet Effects of Aspirin in Healthy Human Subjects

Aspirin is often taken with H2-receptor antagonists. In vitro data suggest that certain antagonists, such as ranitidine, have inhibitory effects on platelet function. There are no reports on the combined effect of aspirin and H2-receptor antagonists on platelet function in humans. Therefore, this study's aim was to evaluate the effects of aspirin, ranitidine, and their combination on platelet function in humans. Ten healthy men aged 34.7 +/- 2 years received aspirin 325 mg/day for 4 days followed by a 9-day washout period, 3 days of ranitidine treatment (150 mg twice daily), and 4 days of dual-drug treatment. Blood samples were drawn at baseline and on the last days of aspirin monotherapy, the washout period, ranitidine monotherapy, and dual-drug treatment. Platelet aggregation was measured in response to 0.5 mg/ml arachidonic acid, 5 and 10 mumol/L adenosine diphosphate, and 1 micro g/ml collagen. The Platelet Function Analyzer 100 test was performed, and blood salicylate levels were measured in 6 subjects. Aspirin caused a marked reduction in platelet aggregation and prolongation of Platelet Function Analyzer 100 closure time. Ranitidine caused a modest decrease in platelet aggregation. Unexpectedly, the combination of aspirin and ranitidine caused less inhibition of platelet aggregation and prolongation of Platelet Function Analyzer 100 time than aspirin alone (p = 0.02 to 0.07 compared with aspirin alone). Blood salicylate levels were lower when subjects took aspirin with ranitidine than when they took aspirin alone (1 +/- 0.8 vs 1.6 +/- 0.7 mg/dl, p = 0.005). In conclusion, ranitidine appears to attenuate the antiplatelet effects of aspirin in healthy volunteers. The most likely mechanism for these findings is a change in the absorption conditions of aspirin in the presence of ranitidine.

Effect of Enteric Coating on Antiplatelet Activity of Low-Dose Aspirin in Healthy Volunteers

Aspirin resistance may be relatively common and associated with adverse outcome. Meta-analysis has clearly shown that 75 mg plain aspirin is the lowest effective dose; however, it is not known whether the recent increased use of enteric-coated aspirin could account for aspirin resistance. This study was designed to determine whether enteric-coated aspirin is as effective as plain aspirin in healthy volunteers. Seventy-one healthy volunteers were enrolled in 3 separate bioequivalence studies. Using a crossover design, each volunteer took 2 different aspirin preparations. Five aspirin preparations were evaluated, 3 different enteric-coated 75-mg aspirins, dispersible aspirin 75 mg and asasantin (25-mg standard release aspirin plus 200-mg modified-release dipyridamole given twice daily). Serum thromboxane (TX) B2 levels and arachidonic acid-induced platelet aggregation were measured before and after 14 days of treatment. All other aspirin preparations tested were inferior to dispersible aspirin (P<0.001) in their effect on serum TXB(2) level. Treatment failure (<95% inhibition serum TXB2 formation) occurred in 14 subjects, none of whom were taking dispersible aspirin. Mean weight for those demonstrating treatment failure was greater than those with complete TXB2 (>99%) inhibition (P<0.001). Using logistic regression analysis an 80-kg subject had a 20% probability of treatment failure. Asasantin was the most potent preparation in terms of inhibition of platelet aggregation. Equivalent doses of the enteric-coated aspirin were not as effective as plain aspirin. Lower bioavailability of these preparations and poor absorption from the higher pH environment of the small intestine may result in inadequate platelet inhibition, particularly in heavier subjects.

High Rate of Aspirin Resistance among Patients Undergoing Per-Cutaneous Intervention for Unstable Angina Is Associated with Clinical Outcome.

The response to anti-platelet therapy may affect clinical outcome in patients with ischemic heart disease. We prospectively investigated the response to aspirin and clopidogrel in unstable angina patients undergoing per-cutaneous intervention (PCI). Platelet function was analyzed using an aggregometer and the Cone and Platelet Analyzer (CPA) tests. In the CPA test, preincubation of blood samples with sub-optimal concentrations of arachidonic acid (AA) or ADP results in decreased platelet deposition under flow. The test was used to evaluate platelet responsiveness to aspirin and clopidogrel. Preliminary studies have demonstrated that this method is useful in detecting the response to aspirin in healthy volunteers. All patients (87) received aspirin treatment prior to hospitalization. On admission, the response to aspirin as tested by the CPA method was unexpectedly low, surface coverage (SC) with AA 2.2±0.2% (mean ± SE), with ADP 1.7±0.2%, reflecting a response rate of 26.9%. Comparable results were obtained using aggregometry, with 33.9±2.6% maximal aggregation in response to AA and 60.7±3.1% maximal aggregation in response to ADP, reflecting a response rate to aspirin of 33.3%. On the second day, after receiving 300 mg clopidogrel, the CPA assay with ADP revealed a significant response to the drug (SC 4.1±0.4%). Moreover, testing with AA on the second day demonstrated an increased response rate to aspirin (SC 4.6±0.3%), suggesting a cooperative effect of the two drugs. These results reflect response rate to aspirin of 75.4% on the second day. Aggregometry testing on the second day revealed an increased response rate up to 84.0% (maximal aggregation with AA 18.3±2.2% and with ADP 23.3±2.2%). A sub-group of 50 patients examined 6 months after the hospitalization demonstrated that the high response rate to aspirin (90%, SC 6.1±0.6%) was preserved nevertheless clopidogrel treatment had been discontinued. At the same time, according to aggregometry with AA, only 68% response rate to aspirin was observed (25.5±3.8% maximal aggregation). The response to ADP in both assays returned to the control level (SC 2.2±0.2%; maximal aggregation 70.5±3.1%), reflecting the fact that all tested patients were off clopidogrel therapy at this point. A prospective clinical evaluation revealed that 7 out of 8 patients who required additional PCI (balloon or stent) during the first 6 months after discharge were unresponsive to aspirin on the day of hospitalization as judged by both methods. In contrast, these patients except one became responders to aspirin on day 2 and after 6 months, as tested by both methods. In conclusion: a) a low response rate to aspirin was observed in patients with unstable angina undergoing PCI; b) loading dose of 300 mg of clopidogrel significantly increased the response to aspirin accordnig to both methods; c) aspirin resistance on admission might predict future complications; d) the CPA test was found useful for monitoring the effects of both aspirin and clopidogrel, and e) clopidogrel therapy before PCI in unstable angina (at least for aspirin resistant patients), may improve clinical outcome.

A trial to assess the clinical mechanistics of aspirin in healthy volunteers

The aim of this study was to assess the pharmacological effects of aspirin on prostanoid biosynthesis — as measured by plasma thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) concentrations — and two physiological functions thought to be mediated via prostanoids, namely gastrointestinal mucosal integrity — as measured by faecal porphyrins — and renal blood flow — as measured by para-aminohippuric acid (PAH) and creatinine clearance. The trial was a randomized, double-blind, placebo-controlled crossover design, with each volunteer taking 750 mg aspirin (British Pharmacopoeia) or placebo, three times a day for 5 days, with an 18-day washout period between treatments. Faecal porphyrins were measured before the first dose and on days 2 to 5 inclusive of each dosing period; plasma TXB2 and PGE2 concentrations were measured before dosing and 0.5 hours after the final dose on day 5 of each of the dosing periods; PAH clearance was measured before dosing and at 90, 120 and 150 min after the start of the infusion of PAH on day 1 and day 5 of each dosing period; creatinine clearance was measured before dosing and prior to the final dose on day 5 of each dosing period.

Celecoxib Does Not Affect the Antiplatelet Activity of Aspirin in Healthy Volunteers

Celecoxib Does Not Affect the Antiplatelet Activity of Aspirin in Healthy Volunteers

Celecoxib Does Not Affect the Antiplatelet Activity of Aspirin in Healthy Volunteers

Celecoxib is a novel cyclooxygenase-2-specific inhibitor for the management of acute pain, primary dysmenorrhea, and the signs and symptoms of arthritis. This double-blind, placebo-controlled study in 16 healthy volunteers evaluated whether celecoxib alters the effect of concomitant aspirin on platelet function. Volunteers received celecoxib (400 mg/day) or placebo for 4 days. On day 5, they also received a single 325 mg dose of aspirin with either 200 mg celecoxib or placebo. Thromboxane and platelet aggregation response to adenosine 5'-diphosphate (ADP), collagen, and arachidonic acid were measured before the first dose of celecoxib or placebo (baseline) and before dosing and 2 and 8 hours post dose on day 5. There was no significant difference in thromboxane inhibition between the two groups (percent inhibition: placebo 99.4%, celecoxib 99.0%; p = 0.555). There was also no significant difference in the effect of aspirin on platelet aggregation due to ADP, collagen, or arachidonic acid between the groups. Therefore, these data indicate that celecoxib does not alter the effects of aspirin on platelet function.