Sex-related differences in the efficacy of acetylsalicylic acid (ASA): The absorption of ASA and its effect on collagen-induced thromboxane B2 generation (original) (raw)
Related papers
Scandinavian Journal of Haematology, 2009
We have used the impedance aggregometer to study the in vitro effect of acetylsalicylic acid (ASA) in whole blood (WB) versus platelet-rich plasma (PRP) using blood samples from 24 male and 24 female healthy volunteers. IC50 was calculated from dose-response curves of ADP-, adrenaline-, collagen- and arachidonic acid-induced aggregation. ASA inhibited platelet aggregation in WB with a lower IC50 than PRP in male and female samples; the greater differences between WB and PRP inhibitory effect of ASA were in collagen- and archidonic acid-induced aggregation. A higher ASA concentration was needed in order to produce half maximal inhibition of platelet aggregation in female than in male samples with both WB and PRP method, except when ADP was used as the aggregating agent in PRP.
Blood Coagulation & Fibrinolysis, 2014
A reliable and simple laboratory assay for predicting clinical effectiveness of antiplatelet acetylsalicylic acid (ASA) therapy is needed. We have compared various laboratory protocols for measuring blood thromboxane A2 (TXA2) generation used to detect the effects of ASA administration. Healthy volunteers (n = 15) were given 150 mg per day ASA for 10 days, followed by ASA at 75 mg per day for 10 days. Five protocols tested for measuring TXA2 generation were: baseline TXB2 determination in plasma; static generation of TXA2 in anticoagulated blood (1 h incubation at room temperature or 37°C, respectively); dynamic generation of TXA2 in anticoagulated blood (1 h in rotary mixer); and generation of TXA2 in blood without anticoagulant (serum-generated TXA2). Platelet aggregation in whole blood was also measured using arachidonic acid (AA), collagen, and ADP as agonists. All five protocols showed significant reduction in TXB2 levels in individuals taking ASA. However, only the assay of TXA2 generation in serum was significantly different compared with the other protocols (P < 0.002). Moreover, the strongest and most significant correlation was observed between TXA2 generation in serum and AA-induced aggregation parameters (for 75 mg per day ASA).Serum TXA2 generation is the best laboratory protocol to detect the effects of ASA, based on serum markers of prostanoid metabolism.
Clinical Pharmacology: Advances and Applications, 2014
The pharmacology of single doses of acetylsalicylic acid (ASA) administered intravenously (250 or 500 mg) or orally (100, 300, or 500 mg) was evaluated in a randomized, placebo-controlled, crossover study. Methods: Blood and urine samples were collected before and up to 24 hours after administration of ASA in 22 healthy volunteers. Pharmacokinetic parameters and measurements of platelet aggregation were determined using validated techniques. Results: A comparison between administration routes showed that the geometric mean dosecorrected peak concentrations (C max /D) and the geometric mean dose-corrected area under the curve (AUC 0-∞ /D) were higher following intravenous administration of ASA 500 mg compared with oral administration (estimated ratios were 11.23 and 2.03, respectively). Complete inhibition of platelet aggregation was achieved within 5 minutes with both intravenous ASA doses, reflecting a rapid onset of inhibition that was not observed with oral dosing. At 5 minutes after administration, the mean reduction in arachidonic acid-induced thromboxane B 2 synthesis ex vivo was 99.3% with ASA 250 mg intravenously and 99.7% with ASA 500 mg intravenously. In exploratory analyses, thromboxane B 2 synthesis was significantly lower after intravenous versus oral ASA 500 mg (P,0.0001) at each observed time point up to the first hour after administration. Concentrations of 6-keto-prostaglandin 1α at 5 and 20 minutes after dosing were also significantly lower with ASA 500 mg intravenously than with ASA 500 mg orally. Conclusion: This study demonstrates that intravenous ASA provides more rapid and consistent platelet inhibition than oral ASA within the first hour after dosing.
Journal of clinical pharmacology, 2015
Acetylsalicylic acid has remained as the antiplatelet therapy basis for more than 50 years. Its basic mechanism of action was described more than 40 years ago, and involves irreversible inhibition of the cyclooxygenase enzyme.[1] More recently, further details of acetylsalicylic acid interaction with cyclooxygenase were described (acetylation of serine 529 residue, blocking the arachidonic acid catalytic site, causing strong suppression of prostaglandin-H2 generation and, subsequently, thromboxane-A2 synthesis).[2, 3] On platelets, this will lead to inhibition of platelet activation by the thromboxane receptor, producing an anti-aggregating effect.[4, 5] Daily dosage commonly prescribed for prevention of myocardial infarction, stroke and death for high risk patients is established between 75 and 325 mg per day.[6, 7] This article is protected by copyright. All rights reserved.
Journal of Thrombosis and Thrombolysis, 2020
Arachidonic acid (AA)-induced platelet aggregation (PA) and serum thromboxane B 2 (TxB 2) inhibition are widely used to indicate cyclooxygenase-1 activity and the antiplatelet effect of acetylsalicylic acid (ASA). Despite decades of investigations, the relation between these measurements remains unclear. We sought to evaluate the relation between AA-PA and serum TxB 2 inhibition. We serially measured AA-PA (conventional aggregation), serum TxB 2, plasma ASA and salicylic acid (SA) (liquid chromatography-mass spectrometry), and urinary 11-dehydro thromboxane B 2 (u11-dh TxB 2) (enzymelinked immunosorbent assay) levels at 10 times over 24 hours in seventeen healthy volunteers receiving a single dose of 162 mg chewed and swallowed ASA (n = 6), 50 mg inhaled ASA (n = 6), or 100 mg inhaled ASA (n = 5) (ClinicalTrials. gov Identifier: NCT04328883, April 1, 2020). Baseline variability was more pronounced with serum TxB 2 (31-680 ng/mL) as compared to maximal AA-PA (65-81%) and u11-dh TxB 2 (1556-4440 pg/mg creatinine). The relation between serum TxB 2 inhibition and AA-PA was stepwise; after 30-40% inhibition of serum TxB 2 , AA-PA fell to < 5%. By receiver operating characteristic curve analysis using AA-PA < 5% to define aspirin responsiveness, serum TxB2 inhibition > 49% and u11-dh TxB2 < 1520 pg/mg creatinine met the definition. Our study demonstrates a non-linear relation between serum TxB 2 inhibition and AA-PA. Aggregation was nil once TxB 2 inhibition reached > 49%. Moreover, these results suggest that the definition of > 95% inhibition of serum TxB 2 to indicate the level of platelet COX-1 inhibition needed for clinical efficacy may be overestimated and should be reconsidered in future translational research investigations that attempt to link the clinical efficacy of ASA with a laboratory measurement cutoff.
International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity, 2003
Platelet aggregation responses to acetylsalicylic acid (ASA) show considerable interindividual variation, the causes of which are largely unknown. We determined whether variation in insulin action is associated with that of ASA on platelets. In all, 10 nonobese (age 50+/-3 y, BMI 25+/-1 kg/m(2)) and 11 obese (age 52+/-2 y, BMI 32+/-1 kg/m(2)) subjects. Insulin sensitivity of glucose uptake was determined by the euglycemic insulin clamp technique. Platelet aggregation responses to four doses of arachidonic acid (AA) and adenosine diphosphate (ADP) were assessed in platelet-rich plasma before and 1 h after ingestion of 50 mg ASA using Born's turbidometric aggregometer. Whole-body insulin sensitivity (M-value 0-180 min) was 36% lower in the obese (4.5+/-0.6) than the nonobese (7.1+/-0.6 mg/kg min, P<0.01) group. Before ASA, all doses of AA induced complete aggregation. After ASA ingestion, ASA inhibited maximal aggregation more in the nonobese than the obese group at AA concentr...
Thrombosis Research, 1999
Abbreviations: ASA, acetylsalicylic acid; EDTA, edetic acid; rationale for its use in cardiovascular disorders is EGTA, egtazic acid; BSA, bovine serum albumin; PMSF, phenylthat the compound inhibits the synthesis of thrommethylsulphonyl fluoride. Corresponding author: N.Y. Maeda, Laborató rio de Biotecnoboxane A 2 by irreversibly blocking platelet cyclologia, Fundaçã o Pró -Sangue Hemocentro de Sã o Paulo, Av. Dr. oxygenase [12]. This study was planned to investi-Ené as C. Aguiar, 155, PAMB -1 Њ andar 05403-000, Sã o Paulo, SP, Brazil. Tel/Fax: ϩ55 (11) 282 2398. gate possible effects of cyclooxygenase blockade 0049-3848/99 $-see front matter
Journal of Thrombosis and Thrombolysis, 2023
Despite decades of investigations, the optimal assessment of the "therapeutic response" to early after loading dose of acetylsalicylic acid (ASA) remains unclear. Limited information is available on the relation between pharmacodynamic (PD) and pharmacokinetic (PK) measurements assessed immediately after ASA administration. Serial PD and PK analyses were performed immediately after a single 162 or 650 mg dose of chewed and swallowed ASA in ten healthy adults. ASA response was defined as > 95% inhibition of serum thromboxane (Tx)B 2, < 550 aspirin reaction units (ARU) by VerifyNow Aspirin (VN) test, and ≤ 20% arachidonic acid (AA)-induced platelet aggregation (PA). Correlation analyses between PK and PD measurements and receiver operating characteristic (ROC) curve analyses were performed. ASA response measured by VN test and AA-induced PA was achieved within 30 min of ASA administration. A correlation was observed between ARU and AA-induced maximum PA (r = 0.69, p < 0.001), serum TxB 2 (r = 0.74 and p < 0.001), and serum TxB 2 inhibition (r = 0.79, p < 0.001). In ROC curve analyses, ≤ 558 ARU and ≤ 7% AA-induced PA were associated with > 95% inhibition of TxB 2. 686 ng/ml plasma ASA cutoff point was associated with > 95% inhibition of serum TxB 2 , ≤ 7% 1 mM AA-induced PA, and ≤ 585 ARU. A modest ~ 50% inhibition of TxB 2 inhibition was associated with marked inhibition of 1 mM AAinduced platelet aggregation by LTA. Our analyses demonstrated important relationships between pharmacodynamic, and pharmacokinetic parameters measured immediately following oral ASA and cutoff values for ARU and AA-induced PA that is associated with > 95% inhibition of serum TxB 2 .