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1.
Am J Hematol ; 99(8): 1462-1474, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38877813

ABSTRACT

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.


Subject(s)
Aspirin , Drug Administration Schedule , Hemorrhage , Platelet Aggregation Inhibitors , Thrombocythemia, Essential , Humans , Aspirin/administration & dosage , Aspirin/therapeutic use , Thrombocythemia, Essential/drug therapy , Thrombocythemia, Essential/blood , Male , Middle Aged , Female , Aged , Adult , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/therapeutic use , Platelet Aggregation Inhibitors/adverse effects , Hemorrhage/chemically induced , Thromboxane B2/blood , Platelet Activation/drug effects , Aged, 80 and over , Treatment Outcome
2.
Sci Rep ; 14(1): 5546, 2024 03 06.
Article in English | MEDLINE | ID: mdl-38448541

ABSTRACT

Biological samples are often frozen and stored for years and/or thawed multiple times, thus assessing their stability on long-term storage and repeated freeze-thaw cycles is crucial. The study aims were to assess:-the long-term stability of two major enzymatic and non-enzymatic metabolites of arachidonic acid, i.e. urinary 11-dehydro-thromboxane-(Tx) B2, 8-iso-prostaglandin (PG)F2α, and creatinine in frozen urine samples;-the effect of multiple freeze-thaw cycles. Seven-hundred and three urine samples measured in previously-published studies, stored at -40 °C, and measured for a second time for 11-dehydro-TxB2 (n = 677) and/or 8-iso-PGF2α (n = 114) and/or creatinine (n = 610) were stable over 10 years and the 2 measurements were highly correlated (all rho = 0.99, P < 0.0001). Urine samples underwent 10 sequential freeze-thaw cycles, with and without the antioxidant 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (10 mM); urinary 11-dehydro-TxB2 and creatinine were stable across all cycles (11-dehydro-TxB2: 100.4 ± 21%; creatinine: 101 ± 7% of baseline at cycle ten; n = 17), while 8-iso-PGF2α significantly increased by cycle 6 (151 ± 22% of baseline at cycle ten, n = 17, P < 0.05) together with hydrogen peroxide only in the absence of antioxidant. Arachidonic acid metabolites and creatinine appear stable in human urines stored at -40 °C over 10 years. Multiple freeze-thaw cycles increase urinary 8-iso-PGF2α in urine samples without antioxidants. These data are relevant for studies using urine samples stored over long-term and/or undergoing multiple freezing-thawing.


Subject(s)
Antioxidants , Prostaglandins F , Humans , Arachidonic Acid , Creatinine , Freezing , Immunoenzyme Techniques , Thromboxanes
3.
Eur Heart J ; 45(15): 1355-1367, 2024 Apr 14.
Article in English | MEDLINE | ID: mdl-38385506

ABSTRACT

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 ∼70% 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.


Subject(s)
Diabetes Mellitus, Type 2 , Neoplasms , Thrombosis , Humans , Female , Thromboxanes/metabolism , Thromboxanes/therapeutic use , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Aspirin/therapeutic use , Thromboxane B2/therapeutic use , Thromboxane B2/urine , Thromboxane A2/therapeutic use , Thromboxane A2/urine , Thrombosis/drug therapy , Neoplasms/drug therapy
4.
Br J Cancer ; 129(4): 706-720, 2023 09.
Article in English | MEDLINE | ID: mdl-37420000

ABSTRACT

BACKGROUND: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases. METHODS: Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values. RESULTS: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg. CONCLUSIONS: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin.


Subject(s)
Aspirin , Colorectal Neoplasms , Female , Humans , Male , Middle Aged , Biomarkers , Colorectal Neoplasms/drug therapy , Creatinine , Thromboxanes/therapeutic use
5.
Clin Transl Sci ; 15(12): 2958-2970, 2022 12.
Article in English | MEDLINE | ID: mdl-36200184

ABSTRACT

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.


Subject(s)
Polycythemia Vera , Humans , Polycythemia Vera/drug therapy , Polycythemia Vera/metabolism , Thromboxanes/metabolism , Thromboxanes/pharmacology , Thromboxanes/therapeutic use , Aspirin/pharmacology , Blood Platelets/metabolism , Thromboxane B2 , Thromboxane A2/metabolism , Thromboxane A2/pharmacology , Computer Simulation , Platelet Aggregation Inhibitors
6.
PLoS One ; 17(8): e0268905, 2022.
Article in English | MEDLINE | ID: mdl-35976924

ABSTRACT

A computational approach involving mathematical modeling and in silico experiments was used to characterize the determinants of extent and duration of platelet cyclooxygenase (COX)-1 inhibition by aspirin and design precision dosing in patients with accelerated platelet turnover or reduced drug bioavailability. To this purpose, a recently developed physiologically-based pharmacokinetics (PK) and pharmacodynamics (PD) model of low-dose aspirin in regenerating platelets and megakaryocytes, was used to predict the main features and determinants of platelet COX-1 inhibition. The response to different aspirin regimens in healthy subjects and in pathological conditions associated with alterations in aspirin PK (i.e., severely obese subjects) or PD (i.e., essential thrombocytemya patients), were simulated. A model sensitivity analysis was performed to identify the main processes influencing COX-1 dynamics. In silico experiments and sensitivity analyses indicated a major role for megakaryocytes and platelet turnover in determining the extent and duration of COX-1 inhibition by once-daily, low-dose aspirin. They also showed the superiority of reducing the dosing interval vs increasing the once-daily dose in conditions of increased platelet turnover, while suggested specific dose adjustments in conditions of possible reduction in drug bioavailability. In conclusion, the consistency of our model-based findings with experimental data from studies in healthy subjects and patients with essential thrombocythemia supports the potential of our approach for describing the determinants of platelet inhibition by aspirin and informing precision dosing which may guide personalized antithrombotic therapy in different patient populations, especially in those under-represented in clinical trials or in those associated with poor feasibility.


Subject(s)
Aspirin , Thrombocythemia, Essential , Aspirin/therapeutic use , Blood Platelets , Humans , Models, Theoretical , Obesity/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Thrombocythemia, Essential/drug therapy
7.
Antioxidants (Basel) ; 11(7)2022 Jul 20.
Article in English | MEDLINE | ID: mdl-35883899

ABSTRACT

Oxidative stress is generated by the imbalance between reactive oxygen species (ROS) formation and antioxidant scavenger system's activity. Increased ROS, such as superoxide anion, hydrogen peroxide, hydroxyl radical and peroxynitrite, likely contribute to the development and complications of atherosclerotic cardiovascular diseases (ASCVD). In genetically modified mouse models of atherosclerosis, the overexpression of ROS-generating enzymes and uncontrolled ROS formation appear to be associated with accelerated atherosclerosis. Conversely, the overexpression of ROS scavenger systems reduces or stabilizes atherosclerotic lesions, depending on the genetic background of the mouse model. In humans, higher levels of circulating biomarkers derived from the oxidation of lipids (8-epi-prostaglandin F2α, and malondialdehyde), as well as proteins (oxidized low-density lipoprotein, nitrotyrosine, protein carbonyls, advanced glycation end-products), are increased in conditions of high cardiovascular risk or overt ASCVD, and some oxidation biomarkers have been reported as independent predictors of ASCVD in large observational cohorts. In animal models, antioxidant supplementation with melatonin, resveratrol, Vitamin E, stevioside, acacetin and n-polyunsaturated fatty acids reduced ROS and attenuated atherosclerotic lesions. However, in humans, evidence from large, placebo-controlled, randomized trials or prospective studies failed to show any athero-protective effect of antioxidant supplementation with different compounds in different CV settings. However, the chronic consumption of diets known to be rich in antioxidant compounds (e.g., Mediterranean and high-fish diet), has shown to reduce ASCVD over decades. Future studies are needed to fill the gap between the data and targets derived from studies in animals and their pathogenetic and therapeutic significance in human ASCVD.

8.
Clin Pharmacol Ther ; 111(4): 939-949, 2022 04.
Article in English | MEDLINE | ID: mdl-34743317

ABSTRACT

Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by enhanced platelet production and thrombotic complications. The inhibition of platelet cyclooxygenase (COX) activity by the standard once-daily aspirin is mostly incomplete due to accelerated thrombopoiesis. The phase II Aspirin Regimens in EsSential thrombocythemia (ARES) trial has recently compared the efficacy of once- vs. twice- or three-times daily low-dose aspirin in inhibiting platelet thromboxane (TX) A2 production, as reflected by serum (s) TXB2 measurements. The present substudy characterized the determinants of the highly variable response to the standard aspirin 100 mg once-daily regimen in fully compliant patients with ET and the effects of the experimental dosing regimens on response variability. By multivariable analysis, the platelet count (directly) and cytoreductive treatment (inversely) were significantly associated with sTXB2 values in 218 patients with ET. However, the platelet count positively correlated with sTXB2 in patients not being treated with cytoreductive drugs (ρ = 0.51, P < 0.01, n = 84), but not in patients on cytoreduction. Patients in the lowest sTXB2 quartile were older, more often on cytoreductive drugs, had lower platelet count and Janus-Associated Kinase2 (JAK2)-V617F allele frequency as compared with patients in the upper sTXB2 quartiles. After 2 weeks of a twice- or 3-times daily aspirin regimen, the association between the platelet count and sTXB2 became similar in cytoreduced and non-cytoreduced patients. In conclusion, the platelet count appears the strongest determinant of TXA2 inhibition by once-daily low-dose aspirin in ET, with different patterns depending of cytoreductive treatment. More frequent aspirin dosing restores adequate platelet inhibition and reduces interindividual variability, independently of cytoreduction.


Subject(s)
Aspirin , Thrombocythemia, Essential , Thromboxanes , Aspirin/administration & dosage , Cytoreduction Surgical Procedures , Humans , Platelet Aggregation Inhibitors , Platelet Count , Thrombocythemia, Essential/drug therapy
9.
Cancer Prev Res (Phila) ; 13(10): 877-888, 2020 10.
Article in English | MEDLINE | ID: mdl-32718943

ABSTRACT

Low-dose aspirin is recommended by the U.S. Preventive Services Task Force for primary prevention of colorectal cancer in certain individuals. However, broader implementation will require improved precision prevention approaches to identify those most likely to benefit. The major urinary metabolite of PGE2, 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), is a biomarker for colorectal cancer risk, but it is unknown whether PGE-M is modifiable by aspirin in individuals at risk for colorectal cancer. Adults (N = 180) who recently underwent adenoma resection and did not regularly use aspirin or NSAIDs were recruited to a double-blind, placebo-controlled, randomized trial of aspirin at 81 or 325 mg/day for 8-12 weeks. The primary outcome was postintervention change in urinary PGE-M as measured by LC/MS. A total of 169 participants provided paired urine samples for analysis. Baseline PGE-M excretion was 15.9 ± 14.6 (mean ± S.D, ng/mg creatinine). Aspirin significantly reduced PGE-M excretion (-4.7 ± 14.8) compared with no decrease (0.8 ± 11.8) in the placebo group (P = 0.015; mean duration of treatment = 68.9 days). Aspirin significantly reduced PGE-M levels in participants receiving either 81 (-15%; P = 0.018) or 325 mg/day (-28%; P < 0.0001) compared with placebo. In 40% and 50% of the individuals randomized to 81 or 325 mg/day aspirin, respectively, PGE-M reduction reached a threshold expected to prevent recurrence in 10% of individuals. These results support that aspirin significantly reduces elevated levels of PGE-M in those at increased colorectal cancer risk to levels consistent with lower risk for recurrent neoplasia and underscore the potential utility of PGE-M as a precision chemoprevention biomarker. The ASPIRED trial is registered as NCT02394769.


Subject(s)
Adenoma/pathology , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Aspirin/therapeutic use , Colorectal Neoplasms/pathology , Dinoprostone/metabolism , Adenoma/drug therapy , Adenoma/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Double-Blind Method , Female , Humans , Male , Middle Aged , Young Adult
10.
Blood ; 136(2): 171-182, 2020 07 09.
Article in English | MEDLINE | ID: mdl-32266380

ABSTRACT

Essential thrombocythemia (ET) is characterized by abnormal megakaryopoiesis and enhanced thrombotic risk. Once-daily low-dose aspirin is the recommended antithrombotic regimen, but accelerated platelet generation may reduce the duration of platelet cyclooxygenase-1 (COX-1) inhibition. We performed a multicenter double-blind trial to investigate the efficacy of 3 aspirin regimens in optimizing platelet COX-1 inhibition while preserving COX-2-dependent vascular thromboresistance. Patients on chronic once-daily low-dose aspirin (n = 245) were randomized (1:1:1) to receive 100 mg of aspirin 1, 2, or 3 times daily for 2 weeks. Serum thromboxane B2 (sTXB2), a validated biomarker of platelet COX-1 activity, and urinary prostacyclin metabolite (PGIM) excretion were measured at randomization and after 2 weeks, as primary surrogate end points of efficacy and safety, respectively. Urinary TX metabolite (TXM) excretion, gastrointestinal tolerance, and ET-related symptoms were also investigated. Evaluable patients assigned to the twice-daily and thrice-daily regimens showed substantially reduced interindividual variability and lower median (interquartile range) values for sTXB2 (ng/mL) compared with the once-daily arm: 4 (2.1-6.7; n = 79), 2.5 (1.4-5.65, n = 79), and 19.3 (9.7-40; n = 85), respectively. Urinary PGIM was comparable in the 3 arms. Urinary TXM was reduced by 35% in both experimental arms. Patients in the thrice-daily arm reported a higher abdominal discomfort score. In conclusion, the currently recommended aspirin regimen of 75 to 100 once daily for cardiovascular prophylaxis appears to be largely inadequate in reducing platelet activation in the vast majority of patients with ET. The antiplatelet response to low-dose aspirin can be markedly improved by shortening the dosing interval to 12 hours, with no improvement with further reductions (EudraCT 2016-002885-30).


Subject(s)
Aspirin/administration & dosage , Cyclooxygenase Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/administration & dosage , Adult , Aged , Aspirin/pharmacokinetics , Cyclooxygenase 1/blood , Cyclooxygenase Inhibitors/pharmacology , Double-Blind Method , Epoprostenol/urine , Humans , Middle Aged , Platelet Aggregation Inhibitors/pharmacokinetics , Thrombocythemia, Essential/blood , Thrombocythemia, Essential/urine
11.
Res Pract Thromb Haemost ; 4(3): 413-421, 2020 Mar.
Article in English | MEDLINE | ID: mdl-32211575

ABSTRACT

BACKGROUND: Acquired von Willebrand factor (VWF) deficiency was described in Philadelphia-negative myeloproliferative neoplasms, especially in essential thrombocythemia (ET). VWF phenotype in contemporary patients with polycythemia vera (PV) remains less explored. OBJECTIVES: To characterize the VWF phenotype in PV and to compare VWF phenotype in PV with matched healthy subjects and ET patients. PATIENTS/METHODS: We studied 48 PV patients, treated according to current recommendations (hematocrit ≤ 45%, on low-dose aspirin prophylaxis); 48 healthy and 41 subjects with ET, all sex, age, and blood group matched. We measured VWF antigen, activity, multimeric pattern, ADAMTS-13, and factor VIII (FVIII) antigen. RESULTS: In patients with PV, VWF antigen and activity were significantly higher than in healthy subjects (antigen: 119[96-137] vs 93[79-107] IU/dL; activity: 114[95-128] vs 90[79-107] IU/dL, respectively, medians and interquartile, P < 0.01), with normal multimeric distribution. ADAMTS-13 levels were similar between patients with PV and healthy subjects. FVIII levels were higher in PV than in healthy subjects (141[119-169] versus 98[88-123] IU/dL, respectively, P < 0.01). By multivariable analysis, JAK2-p.V617F allelic burden, erythrocyte count, and male sex significantly predicted VWF antigen and activity levels. As compared to patients with ET, patients with PV showed similar VWF antigen levels but approximately 40% higher activity (79[49-104] vs 112[93-125] IU/dL, respectively, P < 0.01). CONCLUSIONS: Patients with PV show increased VWF and FVIII levels, predicted by JAK2-p.V617F burden and erythrocyte count. At variance with ET, acquired VWF defect was not observed in PV. High VWF/FVIII levels may sustain the thrombotic diathesis of PV and may be investigated as biomarkers for risk stratification.

12.
Curr Vasc Pharmacol ; 18(3): 204-214, 2020.
Article in English | MEDLINE | ID: mdl-30727897

ABSTRACT

Under physiological conditions, peripheral arteries release endogenous vascular-protective and antithrombotic agents. Endothelial cells actively synthesize vasoactive mediators, which regulate vascular tone and platelet reactivity thus preventing thrombosis. Atherosclerosis disrupts homeostasis and favours thrombosis by triggering pro-thrombotic responses in the vessels, platelet activation, aggregation as well as vasoconstriction, phenomena that ultimately lead to symptomatic lumen restriction or complete occlusion. In the present review, we will discuss the homeostatic role of arterial vessels in releasing vascular-protective agents, such as nitric oxide and prostacyclin, the role of pro- and anti-thrombotic vascular receptors as well as the contribution of circulating platelets and coagulation factors in triggering the pro-thrombotic response(s). We will discuss the pathological consequences of disrupting the protective pathways in the arteries and the pharmacological interventions along these pathways.


Subject(s)
Blood Coagulation , Endothelial Cells/metabolism , Endothelium, Vascular/metabolism , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Peripheral Arterial Disease/blood , Thrombosis/blood , Animals , Anticoagulants/therapeutic use , Arteries/metabolism , Arteries/physiopathology , Blood Coagulation/drug effects , Blood Platelets/metabolism , Endothelial Cells/drug effects , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiopathology , Fibrinolytic Agents/therapeutic use , Humans , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiopathology , Myocytes, Smooth Muscle/drug effects , Peripheral Arterial Disease/diagnosis , Peripheral Arterial Disease/drug therapy , Peripheral Arterial Disease/physiopathology , Platelet Aggregation Inhibitors/therapeutic use , Signal Transduction , Thrombosis/diagnosis , Thrombosis/drug therapy , Thrombosis/physiopathology
13.
Diabetes Metab Res Rev ; 36(2): e3232, 2020 02.
Article in English | MEDLINE | ID: mdl-31671234

ABSTRACT

BACKGROUND: Impaired glucose tolerance (IGT) is associated with increased cardiovascular morbidity and mortality. Enhanced thromboxane (TX)-dependent platelet activation plays a pivotal role in atherothrombosis and characterizes type 2 diabetes mellitus (DM). Whether this also pertains to IGT is currently unknown. We investigated whether TXA2 -dependent platelet activation, as reflected by 11-dehydro-TXB2 (TXM) urinary excretion, is comparably abnormal in IGT as in DM, is persistent over long-term follow-up, changes as a function of metabolic disease progression, and is influenced by food intake. METHODS: We prospectively investigated subjects with IGT (n = 48) and two control groups with DM diagnosed either less than 12 months (n = 60) or 12 months or more (n = 58). RESULTS: Baseline TXM excretion was comparable between subjects with IGT and DM, with no evidence of a circadian variation. During a 36-month follow-up, urinary TXM excretion was stable over time in the DM groups, while tended to increase in subjects with IGT. Increasing urinary TXM excretion over time was observed in the subjects who progressed to diabetes vs nonprogressors. CONCLUSIONS: We conclude that TXA2 -dependent platelet activation was at least as high in IGT as in patients with DM and further increased over time, especially in those who progressed to overt diabetes.


Subject(s)
Diabetes Mellitus, Type 2/physiopathology , Glucose Intolerance/epidemiology , Platelet Activation , Thromboxanes/metabolism , Aged , Biomarkers/analysis , Blood Glucose/analysis , Case-Control Studies , Cross-Sectional Studies , Female , Follow-Up Studies , Glucose Intolerance/metabolism , Glucose Intolerance/pathology , Humans , Italy/epidemiology , Longitudinal Studies , Male , Middle Aged , Prognosis , Prospective Studies
14.
J Cell Mol Med ; 23(10): 7078-7087, 2019 10.
Article in English | MEDLINE | ID: mdl-31429199

ABSTRACT

Several clinical and experimental studies have demonstrated that regular use of aspirin (acetylsalicylic acid, ASA) correlates with a reduced risk of cancer and that the drug exerts direct anti-tumour effects. We have previously reported that ASA inhibits proliferation of human glioblastoma multiforme-derived cancer stem cells. In the present study, we analysed the effects of ASA on nervous system-derived cancer cells, using the SK-N-SH (N) human neuroblastoma cell line as an experimental model. ASA treatment of SK-N-SH (N) dramatically reduced cell proliferation and motility, and induced neuronal-like differentiation, indicated by the appearance of the neuronal differentiation marker tyrosine hydroxylase (TH) after 5 days. ASA did not affect cell viability, but caused a time-dependent accumulation of cells in the G0 /G1 phase of the cell cycle, with a concomitant decrease in the percentage of cells in the G2 phase. These effects appear to be mediated by a COX-independent mechanism involving an increase in p21Waf1 and underphosphorylated retinoblastoma (hypo-pRb1) protein levels. These findings may support a potential role of ASA as adjunctive therapeutic agent in the clinical management of neuroblastoma.


Subject(s)
Aspirin/pharmacology , Cell Differentiation/drug effects , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Neuroblastoma/pathology , Retinoblastoma/metabolism , Signal Transduction , Up-Regulation/drug effects , Cell Cycle/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Models, Biological , Phosphorylation/drug effects , Prostaglandin-Endoperoxide Synthases/metabolism , Signal Transduction/drug effects , Survivin/metabolism
15.
J Thromb Haemost ; 17(6): 885-895, 2019 06.
Article in English | MEDLINE | ID: mdl-30933424

ABSTRACT

BACKGROUND: The prevalence and degree of obesity is rising worldwide, increases cardiovascular risk, modifies body composition and organ function, and potentially affects the pharmacokinetics and/or pharmacodynamics of drugs. OBJECTIVES: To investigate the pharmacodynamics of once-daily low-dose aspirin in healthy obese subjects, and to assess whether body weight (BW) and body mass index (BMI) affect the pharmacology of aspirin. PATIENTS/METHODS: Otherwise healthy, obese (BMI > 30 kg/m2 ) subjects were studied before and after 3-4 weeks of 100-mg once-daily aspirin intake. Aspirin pharmacodynamics were assessed according to serum thromboxane (TX) B2 levels measured at 4 hours, 24 hours (i.e., posologic interval) and 48 hours after the last witnessed intake; age-matched and sex-matched non-obese controls were included. A previously calibrated pharmacokinetic/pharmacodynamic in silico model of aspirin was used to fit serum TXB2 data from obese subjects. At baseline, the major urinary TXA2 and prostacyclin metabolites, urinary isoprostane and plasma inflammatory biomarkers were measured. RESULTS: In 16 obese subjects (aged 47 ± 11 years; BMI of 39.4 ± 5.1 kg/m2 ), residual serum TXB2 values between 4 and 48 hours after aspirin intake were increased 3- to 5-fold as compared with controls. At 24 hours, the residual serum TXB2 level was log-linearly associated with body size over a wide range of BMI and BW values, without any apparent threshold. The in silico model predicted that reduced aspirin bioavailability would be inversely related to body size and rescued by 200 mg of aspirin once daily or 85 mg twice daily. Baseline urinary TXA2 metabolite, isoprostane and plasma C-reactive protein levels were significantly increased in obese subjects. CONCLUSIONS: Obesity is associated with impaired aspirin responsiveness, largely because of body size. Impaired inhibition of platelet activation by conventional low-dose aspirin may affect antithrombotic efficacy.


Subject(s)
Aspirin/administration & dosage , Obesity/blood , Obesity/drug therapy , Platelet Activation/drug effects , Adult , Aspirin/pharmacokinetics , Aspirin/pharmacology , Biological Availability , Biomarkers/blood , Body Mass Index , Body Weight , Case-Control Studies , Computer Simulation , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Models, Biological , Obesity/pathology , Pilot Projects , Proof of Concept Study , Thromboxane A2/biosynthesis , Thromboxane B2/blood
16.
Platelets ; 30(2): 148-157, 2019.
Article in English | MEDLINE | ID: mdl-30759035

ABSTRACT

Higher aspirin doses may be inferior in ticagrelor-treated acute coronary syndrome (ACS) patients and reducing bleeding risk whilst maintaining antithrombotic benefits could improve outcomes. We characterized the pharmacodynamics of a novel dual-antiplatelet-therapy regimen consisting of very-low-dose twice-daily (BD) aspirin with standard-dose ticagrelor. A total of 20 ticagrelor-treated ACS patients entered a randomized crossover to take aspirin 20 mg BD (12-hourly) during one 14-day period and 75 mg once-daily (OD) in the other. After 14 days of treatment, serum thromboxane (TX)B2 and light-transmittance aggregometry were assessed pre- and 2 h post-morning-dose, bleeding time was measured post-dose, and TXA2 and prostacyclin stable metabolites were measured in urine collected 2 h post-morning-dose. Data are expressed as mean ± SD. After 14 days treatment, serum TXB2 levels were significantly greater 2 h post-dosing with aspirin 20 mg BD vs. 75 mg OD (3.0 ± 3.6 ng/mL vs. 0.8 ± 1.9 ng/mL; p = 0.018) whereas pre-dosing levels were not significantly different (3.5 ± 4.1 ng/mL vs. 2.5 ± 3.1 ng/mL, p = 0.23). 1-mmol/L arachidonic acid-induced platelet aggregation was similarly inhibited by both regimens pre-dose (8.5 ± 14.3% vs. 5.1 ± 3.6%, p = 0.24) and post-dose (8.7 ± 14.2% vs. 6.6 ± 5.3%; p = 0.41). Post-dose bleeding time was shorter with 20 mg BD (680 ± 306 s vs. 834 ± 386 s, p = 0.02). Urinary prostacyclin and TX metabolite excretion were not significantly different. In conclusion, compared to aspirin 75 mg OD, aspirin 20 mg BD provided consistent inhibition of platelet TXA2 release and aggregation, and improved post-dose hemostasis, in ticagrelor-treated ACS patients. Further studies are warranted to assess whether this regimen improves the balance of clinical efficacy and safety.


Subject(s)
Acute Coronary Syndrome/drug therapy , Aspirin/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , Aspirin/pharmacology , Female , Hemostasis , Humans , Male , Middle Aged , Platelet Aggregation Inhibitors/pharmacology
17.
J Cell Physiol ; 234(9): 15459-15471, 2019 Sep.
Article in English | MEDLINE | ID: mdl-30701538

ABSTRACT

Several clinical studies indicated that the daily use of aspirin or acetylsalicylic acid reduces the cancer risk via cyclooxygenases (Cox-1 and Cox-2) inhibition. In addition, aspirin-induced Cox-dependent and -independent antitumor effects have also been described. Here we report, for the first time, that aspirin treatment of human glioblastoma cancer (GBM) stem cells, a small population responsible for tumor progression and recurrence, is associated with reduced cell proliferation and motility. Aspirin did not interfere with cell viability but induced cell-cycle arrest. Exogenous prostaglandin E2 significantly increased cell proliferation but did not abrogate the aspirin-mediated growth inhibition, suggesting a Cox-independent mechanism. These effects appear to be mediated by the increase of p21 waf1 and p27 Kip1 , associated with a reduction of Cyclin D1 and Rb1 protein phosphorylation, and involve the downregulation of key molecules responsible for tumor development, that is, Notch1, Sox2, Stat3, and Survivin. Our results support a possible role of aspirin as adjunctive therapy in the clinical management of GBM patients.

18.
Blood Cancer J ; 8(6): 49, 2018 06 01.
Article in English | MEDLINE | ID: mdl-29880847

ABSTRACT

Once-daily (od), low-dose aspirin (75-100 mg) is recommended to reduce the thrombotic risk of patients with essential thrombocytemia (ET). This practice is based on data extrapolated from other high-risk patients and an aspirin trial in polycythemia vera, with the assumption of similar aspirin pharmacodynamics in the two settings. However, the pharmacodynamics of low-dose aspirin is impaired in ET, reflecting accelerated renewal of platelet cyclooxygenase (COX)-1. ARES is a parallel-arm, placebo-controlled, randomized, dose-finding, phase II trial enrolling 300 ET patients to address two main questions. First, whether twice or three times 100 mg aspirin daily dosing is superior to the standard od regimen in inhibiting platelet thromboxane (TX)A2 production, without inhibiting vascular prostacyclin biosynthesis. Second, whether long-term persistence of superior biochemical efficacy can be safely maintained with multiple vs. single dosing aspirin regimen. Considering that the primary study end point is serum TXB2, a surrogate biomarker of clinical efficacy, a preliminary exercise of reproducibility and validation of this biomarker across all the 11 participating centers was implemented. The results of this preliminary phase demonstrate the importance of controlling reproducibility of biomarkers in multicenter trials and the feasibility of using serum TXB2 as a reliable end point for dose-finding studies of novel aspirin regimens.


Subject(s)
Aspirin/administration & dosage , Clinical Protocols , Platelet Aggregation Inhibitors/administration & dosage , Thrombocythemia, Essential/complications , Thrombosis/etiology , Thrombosis/prevention & control , Biomarkers , Disease Management , Female , Humans , Male , Patient Selection , Research Design , Thrombocythemia, Essential/diagnosis , Thrombosis/blood , Thrombosis/diagnosis , Thromboxane B2/blood
19.
Rev. SPAGESP ; 19(1): 49-61, Jan.-Jun. 2018. tab
Article in Portuguese | LILACS, Index Psychology - journals | ID: biblio-957390

ABSTRACT

Esse estudo investigou a relação entre clima familiar e problemas emocionais e comportamentais na infância. Participaram 237 mães, pais ou cuidadores de crianças matriculadas em escolas do ensino fundamental da cidade do Rio de Janeiro. Os dados foram coletados por meio do Inventário de Clima Familiar e do Child Behavior Checklist (CBCL 618). Correlações de Pearson e regressões lineares múltiplas indicaram associação negativa entre apoio e coesão familiar e problemas emocionais/comportamentais infantis. Além disso, conflito e hierarquia relacionaram-se positivamente com estes problemas. Os resultados apontaram para a importância dos processos proximais, em especial do clima familiar, como fatores de proteção para o desenvolvimento infantil.


This study investigated the relationship between family climate and emotional/behavioral problems in childhood. A total of 237 mothers, parents or caregivers of children enrolled in elementary schools in Rio de Janeiro participated in the study. Data were collected through the Family-Climate Inventory and the Child Behavior Checklist (CBCL 6/18). Pearson's correlations and multiple linear regressions indicated a negative association between family support and cohesion and children's emotional/behavioral problems. Thus, conflict and family hierarchy were positively associated with these problems. The results showed the importance of the proximal processes, and especially the family climate, as an important source of protection for children's development.


Este estudio investigó la relación entre el clima familiar y los problemas emocionales/comportamentales en la infancia. Participaran 237 madres, padres o cuidadores de niños matriculados en escuelas del sistema educativo fundamental de Río de Janeiro. Los datos fueron recogidos por medio del Inventario de Clima Familiar y el Child Behavior Checklist (CBCL 6/18). Correlaciones de Pearson y regresiones lineares múltiples indicaran asociación negativa entre apoyo y cohesión familiar y los problemas emocionales y de comportamiento de los niños. Además conflicto y jerarquía presentaran relación positiva con estos problemas. Los resultados indican que los procesos proximales, específicamente el clima familiar, son una importante fuente de protección para el desarrollo de los niños.


Subject(s)
Humans , Male , Female , Child , Behavior , Family , Family Relations
20.
Vascul Pharmacol ; 87: 14-22, 2016 12.
Article in English | MEDLINE | ID: mdl-27765537

ABSTRACT

Low-dose aspirin, alone or in combination, is recommended for the secondary prevention of acute non-cardioembolic ischemic stroke and transient ischemic attack, starting soon after the acute event. Clinically-relevant drug-drug interactions (DDIs) are a major concern of regulatory agencies and practicing physicians. Drug's pharmacodynamics and/or pharmacokinetics account for clinically-relevant DDIs that modify efficacy and/or safety of one or more of the co-administered drugs. Some non-steroidal anti-inflammatory drugs interact with aspirin pharmacodynamics by competing on the drug target, i.e. the platelet's cyclooxygenase-1 protein. Although the molecular mechanism(s) of this DDI and its effect on the degree of platelet inhibition in vitro and ex vivo are well unraveled, nevertheless, the extent to which this DDI impacts on long-term antithrombotic efficacy of aspirin in secondary prevention remains unclear. Aspirin pharmacokinetics does not involve critical cytochrome P450 enzymes nor efflux transporters, therefore clinically-relevant DDIs competing on pharmacokinetic pathways seem unlikely. The co-administration of antiplatelet drugs with serotonin storage reuptake inhibitors can create a synergistic effect with antiplatelet agents on platelet inhibition. Low-dose aspirin, alone or in combination with other antiplatelet agents, remains a cornerstone in treating cerebrovascular disorders. The relatively straightforward pharmacokinetics of aspirin limits DDIs, giving it a unique advantage over most antiplatelet drugs.


Subject(s)
Aspirin/administration & dosage , Platelet Aggregation Inhibitors/administration & dosage , Stroke/prevention & control , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Aspirin/pharmacokinetics , Aspirin/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Drug Synergism , Humans , Ischemic Attack, Transient/prevention & control , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology
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