RESUMEN
Patients with essential thrombocythemia (ET) are treated with once-daily low-dose aspirin to prevent thrombosis, but their accelerated platelet turnover shortens the antiplatelet effect. The short-term Aspirin Regimens in EsSential Thrombocythemia trial showed that twice-daily aspirin dosing restores persistent platelet thromboxane (TX) inhibition. However, the long-term pharmacodynamic efficacy, safety and tolerability of twice-daily aspirin remain untested. We performed a multicenter, randomized, open-label, blinded-endpoint, phase-2 trial in which 242 patients with ET were randomized to 100 mg aspirin twice- or once-daily and followed for 20 months. The primary endpoint was the persistence of low serum TXB2, a surrogate biomarker of antithrombotic efficacy. Secondary endpoints were major and clinically relevant non-major bleedings, serious vascular events, symptom burden assessed by validated questionnaires, and in vivo platelet activation. Serum TXB2 was consistently lower in the twice-daily versus once-daily regimen on 10 study visits over 20 months: median 3.9 ng/mL versus 19.2 ng/mL, respectively; p < .001; 80% median reduction; 95% CI, 74%-85%. No major bleeding occurred. Clinically relevant non-major bleedings were non-significantly higher (6.6% vs. 1.7%), and major thromboses lower (0.8% vs. 2.5%) in the twice-daily versus once-daily group. Patients on the twice-daily regimen had significantly lower frequencies of disease-specific symptoms and severe hand and foot microvascular pain. Upper gastrointestinal pain was comparable in the two arms. In vivo platelet activation was significantly reduced by the twice-daily regimen. In patients with ET, twice-daily was persistently superior to once-daily low-dose aspirin in suppressing thromboxane biosynthesis and reducing symptom burden, with no detectable excess of bleeding and gastrointestinal discomfort.
Asunto(s)
Aspirina , Esquema de Medicación , Hemorragia , Inhibidores de Agregación Plaquetaria , Trombocitemia Esencial , Humanos , Aspirina/administración & dosificación , Aspirina/uso terapéutico , Trombocitemia Esencial/tratamiento farmacológico , Trombocitemia Esencial/sangre , Masculino , Persona de Mediana Edad , Femenino , Anciano , Adulto , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores de Agregación Plaquetaria/efectos adversos , Hemorragia/inducido químicamente , Tromboxano B2/sangre , Activación Plaquetaria/efectos de los fármacos , Anciano de 80 o más Años , Resultado del TratamientoRESUMEN
BACKGROUND: Thromboxane metabolites could indirectly reflect platelet activation, among which 11-dehydro-thromboxane B2 (11dhTxB2) and 11-dehydro-2, 3-dinor thromboxane B2 (11dh23dinorTxB2) are two stable metabolites that are abundant in urine, and both are closely related to disease progression and drug use. However, most clinical application studies have focused on the single indicator of 11dhTxB2. We propose an LC-MS/MS method suitable for routine clinical screening with simultaneous determination of both metabolites and conduct preliminary studies in different populations. METHODS AND RESULTS: The thromboxane metabolites were extracted by liquid-liquid extraction and determined by LC-MS/MS. Reference intervals (RI) were established in 333 healthy adults and validated in 25 patients with coronary atherosclerosis (CA). This LC-MS/MS method was over a wide quantitative range (0.1-10 µmol/L), the imprecision and accuracy were 5.2 %-11 % and 89.3 %-106.5 %, and was suitable for clinical routine quantitative screening. The 95th percentile RI of unire 11dhTxB2 was 1220 (95 % CI: 1048, 1376) pg mg Cr -1, for 11dh23dinorTxB2, RI was 908 (95 % CI: 821, 1102) pg mg Cr -1. For the first time, we found a significant correlation between 11dhTxB2 and 11dh23dinorTxB2 in both healthy adults (r = 0.67, P < 0.001) and CA patients (r = 0.77, P < 0.001). CONCLUSION: The establishment of RI provides a reference for diseases related to platelet activation and the use of drugs, and the first discovery of the correlation between 11dhTxB2 and 11dh23dinorTxB2 in urine provides a new possibilitie for the diagnostic and prognostic of cardiovascular diseases.
Asunto(s)
Activación Plaquetaria , Espectrometría de Masas en Tándem , Tromboxano B2/análogos & derivados , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Valores de Referencia , Tromboxanos/orina , Tromboxanos/metabolismo , Tromboxanos/sangre , Cromatografía Liquida , Anciano , Adulto Joven , Enfermedad de la Arteria Coronaria/orina , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/diagnósticoRESUMEN
Metabolomics is an emerging and powerful bioanalytical method supporting clinical investigations. Serum and plasma are commonly used without rational prioritization. Serum is collected after blood coagulation, a complex biochemical process involving active platelet metabolism. This may affect the metabolome and increase the variance, as platelet counts and function may vary substantially in individuals. A multiomics approach systematically investigating the suitability of serum and plasma for clinical studies demonstrated that metabolites correlated well (n = 461, R2 = 0.991), whereas lipid mediators (n = 83, R2 = 0.906) and proteins (n = 322, R2 = 0.860) differed substantially between specimen. Independently, analysis of platelet releasates identified most biomolecules significantly enriched in serum compared to plasma. A prospective, randomized, controlled parallel group metabolomics trial with acetylsalicylic acid administered for 7 days demonstrated that the apparent drug effects significantly differ depending on the analyzed specimen. Only serum analyses of healthy individuals suggested a significant downregulation of TXB2 and 12-HETE, which were specifically formed during coagulation in vitro. Plasma analyses reliably identified acetylsalicylic acid effects on metabolites and lipids occurring in vivo such as an increase in serotonin, 15-deoxy-PGJ2 and sphingosine-1-phosphate and a decrease in polyunsaturated fatty acids. The present data suggest that plasma should be preferred above serum for clinical metabolomics studies as the serum metabolome may be substantially confounded by platelets.
Asunto(s)
Aspirina , Plaquetas , Metabolómica , Plasma , Humanos , Plaquetas/metabolismo , Plaquetas/efectos de los fármacos , Metabolómica/métodos , Aspirina/farmacología , Plasma/metabolismo , Plasma/química , Suero/metabolismo , Suero/química , Lisofosfolípidos/sangre , Esfingosina/análogos & derivados , Esfingosina/sangre , Metaboloma/efectos de los fármacos , Tromboxano B2/sangre , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/sangre , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Masculino , Femenino , Estudios Prospectivos , AdultoRESUMEN
BACKGROUND: Systemic thromboxane A2 generation, assessed by quantifying the concentration of stable thromboxane B2 metabolites (TXB2-M) in the urine adjusted for urinary creatinine, is strongly associated with mortality risk. We sought to define optimal TXB2-M cutpoints for aspirin users and nonusers and determine if adjusting TXB2-M for estimated glomerular filtration rate (eGFR) in addition to urinary creatinine improved mortality risk assessment. METHODS: Urinary TXB2-M were measured by competitive ELISA in 1363 aspirin users and 1681 nonusers participating in the Framingham Heart Study. Cutpoints were determined for TXB2-M and TXB2-M/eGFR using log-rank statistics and used to assess mortality risk by Cox proportional hazard modeling and restricted mean survival time. Multivariable models were compared using the Akaike Information Criterion (AIC). A cohort of 105 aspirin users with heart failure was used for external validation. RESULTS: Optimized cutpoints of TXB2-M were 1291 and 5609â pg/mg creatinine and of TXB2-M/eGFR were 16.6 and 62.1 filtered prostanoid units (defined as pg·min/creatinine·mL·1.73â m2), for aspirin users and nonusers, respectively. TXB2-M/eGFR cutpoints provided more robust all-cause mortality risk discrimination than TXB2-M cutpoints, with a larger unadjusted hazard ratio (2.88 vs 2.16, AIC P < 0.0001) and greater differences in restricted mean survival time between exposure groups (1.46 vs 1.10 years), findings that were confirmed in the external validation cohort of aspirin users. TXB2-M/eGFR cutpoints also provided better cardiovascular/stroke mortality risk discrimination than TXB2-M cutpoints (unadjusted hazard ratio 3.31 vs 2.13, AIC P < 0.0001). CONCLUSION: Adjustment for eGFR strengthens the association of urinary TXB2-M with long-term mortality risk irrespective of aspirin use.
Asunto(s)
Aspirina , Tromboxanos , Humanos , Pronóstico , Creatinina/orina , Aspirina/uso terapéutico , Tromboxano B2/metabolismo , Riñón/metabolismoRESUMEN
BACKGROUND AND AIMS: Thromboxane (TX) A2, released by activated platelets, plays an important role in atherothrombosis. Urinary 11-dehydro-TXB2 (U-TXM), a stable metabolite reflecting the whole-body TXA2 biosynthesis, is reduced by â¼70% by daily low-dose aspirin. The U-TXM represents a non-invasive biomarker of in vivo platelet activation and is enhanced in patients with diabetes. This study assessed whether U-TXM is associated with the risk of future serious vascular events or revascularizations (SVE-R), major bleeding, or cancer in patients with diabetes. METHODS: The U-TXM was measured pre-randomization to aspirin or placebo in 5948 people with type 1 or 2 diabetes and no cardiovascular disease, in the ASCEND trial. Associations between log U-TXM and SVE-R (n = 618), major bleed (n = 206), and cancer (n = 700) during 6.6 years of follow-up were investigated by Cox regression; comparisons of these associations with the effects of randomization to aspirin were made. RESULTS: Higher U-TXM was associated with older age, female sex, current smoking, type 2 diabetes, higher body size, urinary albumin/creatinine ratio of ≥3 mg/mmol, and higher estimated glomerular filtration rate. After adjustment for these, U-TXM was marginally statistically significantly associated with SVE-R and major bleed but not cancer [hazard ratios per 1 SD higher log U-TXM (95% confidence interval): 1.09 (1.00-1.18), 1.16 (1.01-1.34), and 1.06 (0.98-1.14)]. The hazard ratio was similar to that implied by the clinical effects of randomization to aspirin for SVE-R but not for major bleed. CONCLUSIONS: The U-TXM was log-linearly independently associated with SVE-R in diabetes. This is consistent with the involvement of platelet TXA2 in diabetic atherothrombosis.
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Diabetes Mellitus Tipo 2 , Neoplasias , Trombosis , Humanos , Femenino , Tromboxanos/metabolismo , Tromboxanos/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Aspirina/uso terapéutico , Tromboxano B2/uso terapéutico , Tromboxano B2/orina , Tromboxano A2/uso terapéutico , Tromboxano A2/orina , Trombosis/tratamiento farmacológico , Neoplasias/tratamiento farmacológicoRESUMEN
BACKGROUND AND AIM: This study aimed to assess the association between dietary inflammation index with serum Nitric oxide, Prostacyclin, and Thromboxane B2 among Prinzmetal angina patients and healthy persons. METHODS AND RESULTS: This case-control study was conducted among 120 Prinzmetal angina patients and 120 healthy persons referred to the Ardabil Imam Khomeini Hospital between 2021 and 2022. Blood samples were gained from all study participants for measurement of serum Nitric oxide, Prostacyclin, and Thromboxane B2. The serum Nitric oxide in patients who had higher DII was less than in patients with less dietary inflammation index (ß = -0.75 p = 0.02). The serum Prostacyclin level in patients with greater dietary inflammation index was 0.68 ng/ml less than in patients with less dietary inflammation index (ß = -0.68 p = 0.04). The level of serum Thromboxane B2 had a positive association with dietary inflammation index (ß = 0.81 p = 0.04). CONCLUSION: In Prinzmetal angina patients, more dietary inflammation index can increase the serum Thromboxane B2 and decrease the serum Nitric oxide and Prostacyclin. More clinical trial study is needed to confirm these results.
Asunto(s)
Angina Pectoris Variable , Epoprostenol , Humanos , Tromboxano B2 , Óxido Nítrico , Estudios de Casos y Controles , Inflamación/diagnóstico , Tromboxano A2RESUMEN
Urinary prostaglandin (PG) E metabolite (PGE-M) and 11-dehydro (d)-thromboxane (TX) B2 are biomarkers of cyclooxygenase-dependent prostanoid synthesis. We investigated (1) the effect of aspirin 300 mg daily and eicosapentaenoic acid (EPA) 2000 mg daily, alone and in combination, on urinary biomarker levels and, (2) whether urinary biomarker levels predicted colorectal polyp risk, during participation in the seAFOod polyp prevention trial. Urinary PGE-M and 11-d-TXB2 were measured by liquid chromatography-tandem mass spectrometry. The relationship between urinary biomarker levels and colorectal polyp outcomes was investigated using negative binomial (polyp number) and logistic (% with one or more polyps) regression models. Despite wide temporal variability in PGE-M and 11-d-TXB2 levels within individuals, both aspirin and, to a lesser extent, EPA decreased levels of both biomarkers (74% [P ≤ .001] and 8% [P ≤ .05] reduction in median 11-d-TXB2 values, respectively). In the placebo group, a high (quartile [Q] 2-4) baseline 11-d-TXB2 level predicted increased polyp number (incidence rate ratio [IRR] [95% CI] 2.26 [1.11,4.58]) and risk (odds ratio [95% CI] 3.56 [1.09,11.63]). A low (Q1) on-treatment 11-d-TXB2 level predicted reduced colorectal polyp number compared to placebo (IRR 0.34 [0.12,0.93] for combination aspirin and EPA treatment) compared to high on-treatment 11-d-TXB2 values (0.61 [0.34,1.11]). Aspirin and EPA both inhibit PGE-M and 11-d-TXB2 synthesis in keeping with shared in vivo cyclooxygenase inhibition. Colorectal polyp risk and treatment response prediction by 11-d-TXB2 is consistent with a role for platelet activation during early colorectal carcinogenesis. The use of urinary 11-d-TXB2 measurement for a precision approach to colorectal cancer risk prediction and chemoprevention requires prospective evaluation.
Asunto(s)
Aspirina , Pólipos del Colon , Humanos , Aspirina/farmacología , Aspirina/uso terapéutico , Ácido Eicosapentaenoico , Prostaglandina-Endoperóxido Sintasas , Tromboxano B2/orina , Biomarcadores , Prostaglandinas , Activación PlaquetariaRESUMEN
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)B2, < 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 TxB2 (r = 0.74 and p < 0.001), and serum TxB2 inhibition (r = 0.79, p < 0.001). In ROC curve analyses, ≤ 558 ARU and ≤ 7% AA-induced PA were associated with > 95% inhibition of TxB2. 686 ng/ml plasma ASA cut-off point was associated with > 95% inhibition of serum TxB2, ≤ 7% 1 mM AA-induced PA, and ≤ 585 ARU. A modest ~ 50% inhibition of TxB2 inhibition was associated with marked inhibition of 1 mM AA-induced 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 TxB2.
Asunto(s)
Aspirina , Inhibidores de Agregación Plaquetaria , Adulto , Humanos , Aspirina/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Tromboxano B2 , Agregación Plaquetaria , Tromboxanos , Ácido Araquidónico/farmacología , PlaquetasRESUMEN
BACKGROUND: Low dose aspirin is recommended for prevention of preeclampsia, however there is not consensus on the appropriate dose. Pregnancy specific changes have the potential to impact the pharmacology of aspirin in pregnancy, however there are very limited studies on aspirin pharmacokinetics in pregnancy and none linking pharmacokinetics (PK, drug dose and drug level) to pharmacodynamics (PD, drug dose and physiologic response) in pregnancy. As a result, we do not have a good understanding of the pharmacologic response to aspirin in pregnancy, which has important implications for clinical efficacy. We sought to describe the PK and PD of aspirin through pregnancy and to identify individual covariates that impacted aspirin PK/PD. OBJECTIVE: We sought to describe the PK and PD of aspirin through pregnancy (first and third trimester), to identify covariates that significantly impact aspirin PK and to identify the relationship between aspirin PK and PD. STUDY DESIGN: This is a prospective study of patients at high risk for preeclampsia recommended to take 81 mg aspirin daily. This study involved 3 visits as follows: (1) baseline, first trimester (10-16 weeks of gestation) 6-hour PK visit, done before initiation of aspirin; (2) follow-up 1: 2 to 4 weeks after aspirin initiation; and (3) follow-up 2: third trimester 6-hour PK visit (28-32 weeks of gestation). The following were assessed at each visit: weight or body mass index, platelet function analysis-100 (Siemens), urinary thromboxane B2, serum thromboxane B2, and plasma salicylic acid. The PK visits consisted of blood work done at baseline (predose), administration of 81 mg nonenteric coated aspirin, and then plasma blood level of salicylic acid assessed at 30 minutes and then hourly 1 to 6 hours after dose. Pearson correlation and multivariable regression were used to identify associations between parameters and identify relevant covariates. Log-adjusted values were used for regression analysis. P<.05 was considered statistically significant. RESULTS: Nineteen participants were included with first trimester data, and 16 with third trimester data. There was no statistically significant change in mean PK parameters between the first and third trimester, although there was a trend to lower peak concentration in the third than in the first trimester (P=.08). In multivariable regression, baseline obesity and current body mass index as a continuous measures were negatively associated with log-adjusted peak salicylic acid concentration (-0.28 [-0.46 to -0.11], P=.003 and -0.02 [-0.03 to -0.009], P=.001, respectively) and log-adjusted plasma salicylic acid area under the curve 0 to 6 hours postdose (-0.25 [-0.45 to 0.05], P=.02, -0.04 [-0.07 to -0.01], P=.008 respectively). There was a significant decrease in urinary thromboxane 2 to 4 weeks after aspirin initiation compared with baseline, which correlated with a concomitant increase in platelet function analysis-100 closure time. In multivariable regression model, there was a strong association between plasma salicylic acid concentration (area under the curve 0-6 hours postdose) and urinary thromboxane (B=-3.12 [-5.38 to -1.04], P=.006), and with urinary thromboxane suppression and platelet inhibition, platelet function analysis-100 (-0.23 [-0.31 to -0.14], P<.001). With progressive thromboxane suppression, platelet inhibition (platelet function analysis-100 closure time) increased. Individual comorbidities, including weight, hypertension, and pregestational diabetes (Type I or II), also impacted aspirin response. CONCLUSION: We have demonstrated the relationship between individual factors, plasma concentrations of salicylic acid, thromboxane suppression, and platelet inhibition at a single dose (81 mg) of aspirin taken through pregnancy. Our findings suggest that dose modification of aspirin in pregnancy may help to achieve the optimal response. Our results may be used to facilitate computational modeling to identify optimal dosing, taking into consideration individual factors.
Asunto(s)
Aspirina , Inhibidores de Agregación Plaquetaria , Preeclampsia , Tromboxano B2 , Humanos , Aspirina/farmacocinética , Aspirina/farmacología , Femenino , Embarazo , Adulto , Estudios Prospectivos , Inhibidores de Agregación Plaquetaria/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacología , Tromboxano B2/sangre , Tromboxano B2/orina , Preeclampsia/prevención & control , Primer Trimestre del Embarazo , Tercer Trimestre del Embarazo , Adulto Joven , Índice de Masa CorporalRESUMEN
AIMS: Melatonin is known to inhibit platelet aggregation induced by arachidonic acid (AA). In the present study we investigated whether agomelatine (Ago), an antidepressant with agonist activity at melatonin receptor 1 (MT1) and MT2 could reduce platelets aggregation and adhesion. MAIN METHODS: Human platelets from healthy donors were used to test the in vitro effects of Ago in the presence of different platelet activators. We performed aggregation and adhesion assays, thromboxane B2 (TxB2), cAMP and cGMP measurements, intra-platelet calcium registration and flow cytometry assays. KEY FINDINGS: Our data revealed that different concentrations of Ago reduced AA- and collagen-induced human platelet aggregation in vitro. Ago also reduced AA-induced increase in thromboxane B2 (TxB2) production, intracellular calcium levels and P-selectin expression at plasma membrane. The effects of Ago in AA-activated platelets were likely dependent on MT1 as they were blocked by luzindole (a MT1/MT2 antagonist) and mimicked by the MT1 agonist UCM871 in a luzindole-sensitive manner. The MT2 agonist UCM924 was also able to inhibit platelet aggregation, but this response was not affected by luzindole. On the other hand, although UCM871 and UCM924 reduced collagen-induced platelet aggregation and adhesion, inhibition of collagen-induced platelet aggregation by Ago was not mediated by melatonin receptors because it was not affected by luzindole. SIGNIFICANCE: The present data show that Ago suppresses human platelet aggregation and suggest that this antidepressant may have the potential to prevent atherothrombotic ischemic events by reducing thrombus formation and vessel occlusion.
Asunto(s)
Calcio , Agregación Plaquetaria , Humanos , Receptores de Melatonina/metabolismo , Calcio/metabolismo , Plaquetas/metabolismo , Colágeno/metabolismo , Antidepresivos/farmacología , Tromboxanos/metabolismo , Tromboxano B2/metabolismo , Tromboxano B2/farmacologíaRESUMEN
BACKGROUND: 11-Dehydro-thromboxane B2 (11-dehydro-TXB2) is the final stable metabolite of thromboxane A2 (TXA2) and is involved in thrombus formation. Patients with membranous nephropathy (MN) are prone to thromboembolism events. METHODS: Time-resolved fluorescence immunoassay (TRFIA) for 11-dehydro-TXB2 was established by indirect competitive method. The coated 11-dehydro-TXB2-BSA conjugate was used to bind the 11-dehydro-TXB2 antibody competitively to the 11-dehydro-TXB2 antigen in the samples, followed by Eu3+-labeled goat anti-mouse IgG antibody, to detect 11-dehydro-TXB2. This study measured 11-dehydro-TXB2 concentrations in serum samples from healthy individuals and patients with MN. RESULTS: The linear range of TRFIA was 16.38-2000 pg/mL, the sensitivity was 4.70 pg/mL, the average coefficients of variation from intra-assay and inter-assay were 3.50% and 4.95%, respectively, and the recovery was 99.38%. The serum level of 11-dehydro-TXB2 in patients with MN was significantly higher than that in healthy subjects (P < 0.05). The serum 11-dehydro-TXB2 concentration detected by TRFIA was highly consistent with that by ELISA (ρ = 0.900). DISCUSSION: This study successfully established a new highly sensitive method for the detection of 11-dehydro-TXB2 in serum. 11-Dehydro-TXB2 has great potential in evaluating the risk of thromboembolic events in patients with MN and is expected to be applied to other thromboembolic-related diseases.
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Glomerulonefritis Membranosa , Humanos , Glomerulonefritis Membranosa/diagnóstico , Tromboxano B2/metabolismo , Ensayo de Inmunoadsorción Enzimática , AnticuerposRESUMEN
BACKGROUND: Aspirin is widely used for cardioprotection with its antiplatelet effects due to the blocking of thromboxane A2 production. However, it has been suggested that platelet abnormalities in those with diabetes prevent adequate suppression with once daily aspirin. METHODS: In the ASCEND randomized double-blind trial of aspirin 100 mg once daily versus placebo in participants with diabetes but no history of cardiovascular disease, suppression was assessed by measuring 11-dehydro-thromboxane B2 excretion in urine (U-TXM) in a randomly selected sample of 152 participants (76 aspirin arm, 74 placebo arm), plus 198 (93 aspirin arm, 105 placebo arm) adherent to study drugs and selected to maximize the numbers ingesting their last tablet 12-24 h before urine sampling. U-TXM was assayed using a competitive ELISA assay in samples mailed a mean of 2 years after randomization, with time since taking last aspirin/placebo tablet recorded at the time of sample provision. Effective suppression (U-TXM < 1500 pg/mg creatinine) and percentage reductions in U-TXM by aspirin allocation were compared. RESULTS: In the random sample, U-TXM was 71% (95% CI 64-76%) lower among aspirin vs placebo-allocated participants. Among adherent participants in the aspirin arm, U-TXM was 72% (95% CI 69-75%) lower than in the placebo arm and 77% achieved effective suppression overall. Suppression was similar among those who ingested their last tablet more than 12 h before urine sampling with levels in the aspirin arm 72% (95% CI 67-77%) lower than in the placebo arm and 70% achieving effective suppression. CONCLUSIONS: Daily aspirin significantly reduces U-TXM in participants with diabetes, including at 12-24 h after ingestion. TRIAL REGISTRATION: ISRCTN ISRCTN60635500. Registered on 1 Sept 2005; ClinicalTrials.gov NCT00135226. Registered on 24 Aug 2005.
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Enfermedades Cardiovasculares , Diabetes Mellitus , Humanos , Aspirina , Tromboxano B2RESUMEN
STUDY OBJECTIVE: Aspirin (ASA) has demonstrated inconsistent results in primary prevention of cardiovascular disease (CVD). Guidelines are also inconsistent in the recommendation of routine ASA use for primary prevention of CVD, but advocate dosing as a "one-size-fits-all" approach. DESIGN: An intention-to-treat, double-blind, randomized, controlled, clinical trial comparing three treatment arms of ASA 81, 325, and 500 mg daily dosed for 14 days were evenly randomized across the dosing categories to measure the impact of dosing by body mass index (BMI) (20-24.9, 25-29.9, ≥30 kg/m2 ) on ASA anti-platelet effects. SETTING: University Ambulatory Clinic. PATIENTS: Healthy volunteers defined as individuals who were medication free without acute or chronic significant health problems. INTERVENTION: Change in ASA reactivity unit (ARU), salicylate levels, and thromboxane B2 (TxB2) levels were measured across BMI dosing categories and time. MAIN RESULTS: Fifty-four participants with a mean (±SD) age of 34.4 ± 10.9 years (M:F; 23:31) completed the study. Baseline ARU and TxB2 levels were not significantly different between obese and non-obese individuals. BMI was not a predictor of platelet inhibition. There was no interaction between gender and platelet activation at baseline or following ASA treatment. ASA 81 mg was associated with a lower ARU response (approximate 50% lower response) than either the 325-mg or the 500-mg doses of ASA. TxB2 and salicylate levels exhibited lower trends at 81 mg compared with higher doses. CONCLUSIONS: In healthy male and female participants administered ASA for 14 days, obesity is not associated with increased basal platelet activation or ASA resistance. ASA 81 mg was significantly less effective in reducing platelet aggregation compared with ASA 325 and 500 mg, independent of BMI.
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Enfermedades Cardiovasculares , Inhibidores de Agregación Plaquetaria , Humanos , Masculino , Femenino , Adulto Joven , Adulto , Persona de Mediana Edad , Índice de Masa Corporal , Voluntarios Sanos , Estudios Prospectivos , Aspirina , Tromboxano B2 , Obesidad/tratamiento farmacológico , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/tratamiento farmacológicoRESUMEN
This study aimed to assess the association between adherence to the Mediterranean diet with serum Nitric oxide, Prostacyclin, and Thromboxane B2 among Prinzmetal angina patients and healthy persons. This case-control study was conducted among 100 Prinzmetal angina patients and 100 healthy persons referred to the Ardabil Imam Khomeini hospital between 2021 and 2022. Blood samples were obtained from all study participants for measurement of serum Nitric oxide, Prostacyclin, and Thromboxane B2. To calculate adherence to the Mediterranean diet, the ten-item screener was used. The serum Nitric oxide in patients who adhered more to the Mediterranean diet was higher than patients with less adherence (coeff. = 0.41 p = 0.04). The serum Prostacyclin level in patients with greater adherence to the Mediterranean diet was 0.34 units higher than patients with less adherence (coeff. = 0.34 p = 0.02). The level of serum Thromboxane B2 had a negative association with adherence to the Mediterranean diet (coeff. = -0.48 p = 0.04). The amount of consumption of olive oil, fruits, vegetables, and legumes in healthy people was more than Prinzmetal angina patients. In Prinzmetal angina patients, more adherence to the Mediterranean diet can decrease the serum Thromboxane B2 and increase the serum Nitric oxide and Prostacyclin.
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Angina Pectoris Variable , Dieta Mediterránea , Humanos , Epoprostenol , Tromboxano B2 , Óxido Nítrico , Estudios de Casos y Controles , VerdurasRESUMEN
Ethanol and resveratrol have been shown to inhibit platelet aggregation. The aim of this study was to determine whether resveratrol has an additional effect on ethanol-induced inhibition of platelet aggregation. Ca2+ entry and subsequent aggregation of human platelets were measured by the fluorescence method and light transmittance method, respectively. Thromboxane B2 concentrations in media containing platelets were measured by using the enzyme-linked immunosorbent assay. Platelet aggregation induced by thrombin (0.025 U/ml) was significantly inhibited by preincubation of platelets with ethanol (0.5%). Preincubation with resveratrol (3.125 µM), which did not affect thrombin-induced platelet aggregation, significantly augmented the inhibitory effect of ethanol on platelet aggregation. Similar synergic effects of ethanol and resveratrol were found on aggregatory responses to collagen (2 µg/ml) and arachidonic acid (0.25 mM). On the other hand, the thrombin-induced increase in intracellular Ca2+ concentration ([Ca2+]i) was not affected by ethanol alone, resveratrol alone or both ethanol and resveratrol together. In nominally Ca2+-free medium, arachidonic acid (0.75 mM) caused a potent platelet aggregation, which was not affected by the presence of ethanol alone, resveratrol alone, or both of them together. Thromboxane B2 formation induced by thrombin was significantly inhibited by ethanol (0.5%) alone and resveratrol (3.125 µM) alone, and these inhibitory effects were significantly augmented in the presence of both ethanol and resveratrol together. Resveratrol shows an additive effect on ethanol-induced inhibition of platelet aggregation. This effect by resveratrol is partly explained by its inhibitory action on thromboxane A2 production in platelets. In addition, both ethanol and resveratrol attenuate platelet aggregation through acting on the Ca2+-dependent intra-platelet pathway after an increase in [Ca2+]i induced by thrombin.
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Agregación Plaquetaria , Trombina , Humanos , Resveratrol/farmacología , Resveratrol/metabolismo , Trombina/farmacología , Trombina/metabolismo , Ácido Araquidónico/farmacología , Ácido Araquidónico/metabolismo , Etanol/farmacología , Etanol/metabolismo , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/metabolismo , Plaquetas/metabolismo , Tromboxano B2RESUMEN
As a result of SARS-CoV-2 infection, inflammation develops, which promotes oxidative stress, leading to modification of phospholipid metabolism. Therefore, the aim of this study is to compare the effects of COVID-19 on the levels of phospholipid and free polyunsaturated fatty acids (PUFAs) and their metabolites produced in response to reactions with reactive oxygen species (ROS) and enzymes (cyclooxygenases-(COXs) and lipoxygenase-(LOX)) in the plasma of patients who either recovered or passed away within a week of hospitalization. In the plasma of COVID-19 patients, especially of the survivors, the actions of ROS and phospholipase A2 (PLA2) cause a decrease in phospholipid fatty acids level and an increase in free fatty acids (especially arachidonic acid) despite increased COXs and LOX activity. This is accompanied by an increased level in lipid peroxidation products (malondialdehyde and 8-isoprostaglandin F2α) and lipid mediators generated by enzymes. There is also an increase in eicosanoids, both pro-inflammatory as follows: thromboxane B2 and prostaglandin E2, and anti-inflammatory as follows: 15-deoxy-Δ-12,14-prostaglandin J2 and 12-hydroxyeicosatetraenoic acid, as well as endocannabinoids (anandamide-(AEA) and 2-arachidonylglycerol-(2-AG)) observed in the plasma of patients who recovered. Moreover, the expression of tumor necrosis factor α and interleukins (IL-6 and IL-10) is increased in patients who recovered. However, in the group of patients who died, elevated levels of N-oleoylethanolamine and N-palmitoylethanolamine are found. Since lipid mediators may have different functions depending on the onset of pathophysiological processes, a stronger pro-inflammatory response in patients who have recovered may be the result of the defensive response to SARS-CoV-2 in survivors associated with specific changes in the phospholipid metabolism, which could also be considered a prognostic factor.
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COVID-19 , Endocannabinoides , Ácidos Araquidónicos/metabolismo , Dinoprostona/metabolismo , Eicosanoides/metabolismo , Endocannabinoides/metabolismo , Ácidos Grasos no Esterificados , Hospitalización , Hospitales , Humanos , Ácidos Hidroxieicosatetraenoicos , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Peroxidación de Lípido , Lipooxigenasa/metabolismo , Malondialdehído , Fosfolipasas A2/metabolismo , Fosfolípidos/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , SARS-CoV-2 , Sobrevivientes , Tromboxano B2 , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Low-dose aspirin is currently recommended for patients with polycythemia vera (PV), a myeloproliferative neoplasm with increased risk of arterial and venous thromboses. Based on aspirin pharmacodynamics in essential thrombocythemia, a twice-daily regimen is recommended for patients with PV deemed at particularly high thrombotic risk. We investigated the effects of low-dose aspirin on platelet cyclooxygenase activity and in vivo platelet activation in 49 patients with PV, as assessed by serum thromboxane (TX) B2 and urinary TXA2 /TXB2 metabolite (TXM) measurements, respectively. A previously described pharmacokinetic-pharmacodynamic in silico model was used to simulate the degree of platelet TXA2 inhibition by once-daily (q.d.) and twice-daily (b.i.d.) aspirin, and to predict the effect of missing an aspirin dose during q.d. and b.i.d. regimens. Serum TXB2 averaged 8.2 (1.6-54.7) ng/ml and significantly correlated with the platelet count (γ = 0.39) and urinary TXM (γ = 0.52) in multivariable analysis. One-third of aspirin-treated patients with PV displayed less-than-maximal platelet TXB2 inhibition, and were characterized by significantly higher platelet counts and platelet-count corrected serum TXB2 than those with adequate inhibition. Eight patients with PV were sampled again after 12 ± 4 months, and had reproducible serum TXB2 and urinary TXM values. The in silico model predicted complete inhibition of platelet-derived TXB2 by b.i.d. aspirin, a prediction verified in a patient with PV with the highest TXB2 value while on aspirin q.d. and treated short-term with a b.i.d. regimen. In conclusion, one in three patients with PV on low-dose aspirin display less-than-maximal inhibition of platelet TXA2 production. Serum TXB2 measurement can be a valuable option to guide precision dosing of antiplatelet therapy in patients with PV.
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Policitemia Vera , Humanos , Policitemia Vera/tratamiento farmacológico , Policitemia Vera/metabolismo , Tromboxanos/metabolismo , Tromboxanos/farmacología , Tromboxanos/uso terapéutico , Aspirina/farmacología , Plaquetas/metabolismo , Tromboxano B2 , Tromboxano A2/metabolismo , Tromboxano A2/farmacología , Simulación por Computador , Inhibidores de Agregación PlaquetariaRESUMEN
BACKGROUND AND PURPOSE: Uncertainty remains regarding the impact of enteric-coated aspirin (EC-ASA) on secondary prevention of ischemic stroke compared to plain aspirin (P-ASA). Hence, this study was designed to investigate the effect of EC formulation on ASA response via evaluating thromboxane B2 (TXB2) levels in patients with suspected or newly diagnosed stroke. METHODS: A prospective cohort study on suspected or newly diagnosed ischemic stroke patients who are aspirin-naive was conducted. Patients were received either EC aspirin or plain aspirin for at least 3 days. The primary outcome was the proportion of aspirin non-responsiveness between two groups (level of residual serum TXB2 associated with elevated thrombotic risk (< 99.0% inhibition or TXB2 > 3.1 ng/ml) within 72 h after three daily aspirin doses, while secondary outcomes were the incidence of early gastrointestinal tract (GIT) bleeding with the various aspirin preparations. (Trial registration: Clinicaltrials.gov NCT04330872 registered on 02 April 2020). RESULTS: Of 42 patients, ischemic strokes were confirmed in both P-ASA (81%) and EC-ASA (67%) arms. ASA non-responsiveness showed no significant difference between the two formulations (P-ASA vs. EC-ASA; 28.6% vs 23.8%; P = 0.726). Univariate and multivariate logistic regression analysis showed that patients treated with EC-ASA were more likely to have a lower rate of non-responders compared to P-ASA (unadjusted OR 0.78; 95% CI 0.20, 3.11); with the risk highest in type 2 diabetic patients with HBA1c > 6.5% (adjusted OR 6; 95% CI 1.02, 35.27; P = 0.047). No incidence of GIT bleeding observed throughout the study. CONCLUSION: A significant proportion of ASA non-responsiveness was recorded regardless of ASA formulation administered. The increased risk of ASA non-responsiveness in diabetic patients needs further exploration by larger prospective studies.
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Aspirina , Accidente Cerebrovascular Isquémico , Aspirina/efectos adversos , Hemorragia Gastrointestinal/inducido químicamente , Hemoglobina Glucada , Humanos , Inhibidores de Agregación Plaquetaria/efectos adversos , Estudios Prospectivos , Tromboxano B2RESUMEN
OBJECTIVES: To evaluate the effect of aspirin 80 mg compared to placebo on platelet function tests in the second and third trimester of pregnancy. STUDY DESIGN: An explorative study was performed to assess laboratory platelet function in a subpopulation of the APRIL trial: a randomized double-blind trial comparing aspirin 80 mg once daily to placebo for the prevention of recurrent preterm birth. Platelet function was measured between 18 and 22, and between 28 and 32 weeks gestational age with three platelet function tests: VerifyNow®, Chronolog light transmission aggregometry (Chronolog LTA) and serum thromboxane B2 (TxB2). Medication adherence was evaluated by pill counts, self-reported diaries and structured interviews. RESULTS: We included 11 women, six in the aspirin and five in the placebo group. In women receiving aspirin, platelet function was significantly lower compared to women receiving placebo for all three tests: VerifyNow® Aspirin Reaction Units (450.5 vs 648.0, p = 0.017); Chronolog LTA (9.5% vs 94.5%, p = 0.009); serum TxB2 levels (11.9 ng/mL versus 175.9 ng/mL, p = 0.030). For all three tests, platelet function did not differ between the second and third trimester of pregnancy in the aspirin group. In the placebo group, serum TxB2 levels were significantly higher in the third trimester. One non-adherent participant in the aspirin group showed results similar to the placebo group. CONCLUSION: Aspirin 80 mg has a clear inhibitory effect on laboratory platelet function during pregnancy compared to placebo. This effect is similar in the second and third trimester of pregnancy.