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1.
Int J Mol Sci ; 22(21)2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34769074

RESUMO

Cardiovascular diseases are currently among the leading causes of morbidity and mortality in many developed countries. They are distinguished by chronic and latent development, a course with stages of worsening of symptoms and a period of improvement, and a constant potential threat to life. One of the most important disorders in cardiovascular disease is ischemic stroke. The causes of ischemic stroke can be divided into non-modifiable and modifiable causes. One treatment modality from a neurological point of view is acetylsalicylic acid (ASA), which blocks cyclooxygenase and, thus, thromboxane synthesis. The legitimacy of its administration does not raise any doubts in the case of the acute phase of stroke in patients in whom thrombolytic treatment cannot be initiated. The measurement of thromboxane B2 (TxB2) in serum (a stable metabolic product of TxA2) is the only test that measures the effect of aspirin on the activity of COX-1 in platelets. Measurement of thromboxane B2 may be a potential biomarker of vascular disease risk in patients treated with aspirin. The aim of this study is to present the role of thromboxane B2 in ischemic stroke and to present effective therapies for the treatment of ischemic stroke. Scientific articles from the PubMed database were used for the work, which were selected on the basis of a search for "thromboxane and stroke". Subsequently, a restriction was introduced for works older than 10 years, those concerning animals, and those without full text access. Ultimately, 58 articles were selected. It was shown that a high concentration of TXB2 may be a risk factor for ischemic stroke or ischemic heart disease. However, there is insufficient evidence to suggest that thromboxane could be used in clinical practice as a marker of ischemic stroke. The inclusion of ASA in the prevention of stroke has a beneficial effect that is associated with the effect on thromboxane. However, its insufficient power in 25% or even 50% of the population should be taken into account. An alternative and/or additional therapy could be a selective antagonist of the thromboxane receptor. Thromboxane A2 production is inhibited by estrogen; therefore, the risk of CVD after the menopause and among men is higher. More research is needed in this area.


Assuntos
AVC Isquêmico/metabolismo , Tromboxano B2/metabolismo , Animais , Aspirina/uso terapêutico , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Fibrinolíticos/uso terapêutico , Humanos , AVC Isquêmico/sangue , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/fisiopatologia , Tromboxano B2/sangue
2.
Thromb Res ; 208: 92-98, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34742142

RESUMO

BACKGROUND: Aspirin non-response due to persistent platelet reactivity has been associated with adverse vascular events. Light transmission aggregometry (LTA), the 'gold standard' for measuring the platelet response to aspirin therapy, is a cumbersome procedure and a simple and reliable alternative is required. Our aim was to explore whether serum thromboxane B2 (sTXB2) and soluble P-selectin can be used to identify patients who are at risk of increased platelet reactivity while on aspirin. METHODS AND RESULTS: We recruited 293 ischemic stroke patients, taking aspirin for more than seven days, and performed LTA to classify them. Based on therapeutic serum salicylate levels, 63 patients were excluded due to suspected non-compliance, followed by ELISA measurement of TXB2 and P-selectin in serum. Accordingly, patients were classified into 'Responders' (n = 122, 53%), 'Semi-responders' (n = 76, 33%) and 'Non-responders' (n=32, 14%) by LTA. Patients who had platelet aggregation of ≥70% with 10µM ADP and ≥20% with 0.5mM AA were defined as 'Non-responders'. In comparison with 'Responders', 'Non-responders' had 8.63-fold increased risk of secondary vascular events (p = 0.008). ROC curve analysis revealed that sTXB2, at a cut-off level of >4.15 ng/mL, could distinguish the patient group with elevated platelet reactivity with a sensitivity of 84.3% (AUC = 0.84), and was in fair agreement with the LTA-based classification of patients. Soluble P-selectin levels, on the other hand, had no discriminatory ability. CONCLUSION: We suggest sTXB2 measurement as an alternative to the LTA approach for identifying aspirin-treated ischemic stroke patients who are at risk of enhanced platelet reactivity and subsequent vascular events.


Assuntos
Aspirina , Isquemia Encefálica , AVC Isquêmico , Selectina-P/sangue , Tromboxano B2/sangue , Aspirina/uso terapêutico , Isquemia Encefálica/sangue , Isquemia Encefálica/diagnóstico , Humanos , AVC Isquêmico/sangue , AVC Isquêmico/diagnóstico
3.
Eur J Clin Pharmacol ; 77(12): 1815-1823, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34331551

RESUMO

PURPOSE: This study aimed to investigate the pharmacodynamic effects of indobufen and low-dose aspirin in patients with coronary atherosclerosis. METHODS: In the first phase, 218 patients with coronary atherosclerosis were randomly assigned to receive aspirin 100 mg once daily (standard dose); 100 mg once every 2 days; 100 mg once every 3 days; 50 mg twice daily; 75 mg once daily; 50 mg once daily; or indobufen 100 mg twice daily for 1 month. In the second phase, 20 healthy subjects were treated with indobufen 100 mg twice daily for 1 week followed after a 2-week washout by aspirin 100 mg once daily for 1 week. The primary outcome was arachidonic acid-induced platelet aggregation (PLAA), and the secondary outcomes included plasma thromboxane B2 (TXB2) and urinary 11-dehydro-TXB2 (11-dh-TXB2) levels at the end of each treatment.  RESULTS: In the first phase, compared with aspirin 100 mg once daily: all aspirin groups had similar suppression of PLAA whereas indobufen group had significantly less suppressed PLAA. Aspirin given every second or third day, and indobufen produced less suppression of plasma TXB2. All treatment regimens produced similar inhibition of 11-dh-TXB2. In the second phase, compared with aspirin, indobufen produced less suppression of plasma TXB2 at 8 h and 12 h after the last dose. CONCLUSIONS: Aspirin 50 mg twice daily, 75 mg once daily, and aspirin 50 mg once daily produce antiplatelet effects that are similar to aspirin 100 mg once daily. Aspirin given less often than once daily and indobufen 100 mg twice daily do not suppress platelets as effectively as aspirin 100 mg once daily.


Assuntos
Aspirina/farmacologia , Doença da Artéria Coronariana/tratamento farmacológico , Isoindóis/farmacologia , Fenilbutiratos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Idoso , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Tromboxano B2/análogos & derivados , Tromboxano B2/sangue , Tromboxano B2/urina
4.
Nutr Res ; 86: 37-49, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33482597

RESUMO

Preeclampsia is a pregnancy-specific disorder, leading to maternal and infant morbidity and mortality. Abnormal placentation has been reported in preeclampsia. Nutrients like vitamin D and long-chain polyunsaturated fatty acids (LCPUFA) are known to play a role in placental development. In an animal model, we have previously demonstrated that maternal vitamin D deficiency increases the thromboxane/prostacyclin ratio and contributes to inflammation and vasoconstriction. We hypothesize that maternal vitamin D status influences placental LCPUFA metabolism through alterations in one carbon metabolism in women with preeclampsia. To test this hypothesis, we recruited 69 normotensive control (NC) women and 50 women with preeclampsia. Women with preeclampsia had lower placental protein and mRNA levels of cystathionine-ß-synthase (CBS), higher plasma malondialdehyde (MDA) levels and higher levels of arachidonic acid (AA) and total omega-6 fatty acids in the placenta. Women with preeclampsia also demonstrated higher placental mRNA levels of cyclooxygenase-2 (COX-2) as compared to NC women. Maternal 25(OH)D levels were negatively associated with maternal plasma MDA levels. Placental vitamin D receptor (VDR) levels were positively associated with CBS while maternal MDA levels were positively associated with serum levels of thromboxane-B2 (TXB2) levels. Our findings indicate that vitamin D deficiency increases oxidative stress through alterations in one carbon metabolism to influence pro-inflammatory omega-6 metabolic pathway in the placenta. This study demonstrates a possible mechanism through which vitamin D deficiency can result in an imbalance in the LCPUFA metabolites and contribute to placental inflammation and endothelial dysfunction in preeclampsia.


Assuntos
Ácidos Graxos Insaturados/metabolismo , Pré-Eclâmpsia/metabolismo , Resultado da Gravidez , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/metabolismo , Adolescente , Adulto , Estudos Transversais , Ácidos Graxos/metabolismo , Feminino , Humanos , Recém-Nascido , Malondialdeído/sangue , Estresse Oxidativo , Placenta/metabolismo , Pré-Eclâmpsia/sangue , Gravidez , Receptores de Calcitriol/metabolismo , Tromboxano B2/sangue , Vitamina D/análogos & derivados , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Adulto Jovem
5.
Shock ; 55(1): 121-127, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32433211

RESUMO

BACKGROUND: Our previous study demonstrated the types of platelet dysfunction varied at early stage (∼3 h) in trauma-induced coagulopathy (TIC) caused by different types of injuries. And arachidonic acid (AA)-dependent pathway inhibition in platelet seemed to be specific for TIC caused by multiple injury (MI). The aim of this research was to further study AA-dependent pathway inhibition in platelets in a rat model of TIC caused by MI and to explore its potential mechanisms. METHODS: Sprague-Dawley rat model of TIC caused by MI was established. We used thrombelastography with platelet mapping as a measure of platelet function to assess the inhibitory extent of AA-dependent activation pathway. Flow cytometry was used to determine the expression of activation-dependent granular protein P-selectin (CD62P). In addition, the plasma levels of 6-Keto-prostaglandin F1 alpha (6-Keto-PGF1α), Prostaglandin E2, and Thromboxane B2 were assessed by enzyme-linked immuno sorbent assay. RESULTS: The inhibition rate of AA-dependent pathway after injury was significantly higher than that of control. The maximum amplitude decreased in the MI group, compared with that of control. The percentage of CD62P expression in the MI group was remarkably lower than that of control after AA treatment. The plasma concentrations of 6-Keto-PGF1α and PGE2 increased in the MI group. CONCLUSION: Platelets inhibition was observed in TIC caused by MI at early stage after injury, which might be partially attributed to AA-dependent activation pathway dysfunction. The increase of plasma Prostacyclin and PGE2 levels may contribute to the inhibition process.


Assuntos
Ácido Araquidônico/metabolismo , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/etiologia , Traumatismo Múltiplo/sangue , Traumatismo Múltiplo/complicações , Ativação Plaquetária/fisiologia , 6-Cetoprostaglandina F1 alfa/sangue , Animais , Plaquetas , Dinoprostona/sangue , Modelos Animais de Doenças , Epoprostenol/sangue , Masculino , Selectina-P/sangue , Testes de Função Plaquetária , Ratos , Ratos Sprague-Dawley , Tromboelastografia , Tromboxano B2/sangue
6.
Am J Cardiovasc Drugs ; 21(1): 63-71, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32394295

RESUMO

BACKGROUND: Acetylsalicylic acid (ASA) is a frequently used antiplatelet agent, although some individuals have reduced antiplatelet responses on ASA, with recurrent ischemic events. It has been proposed that shortening the ASA dosing interval may overcome the time-dependent renewal of the drug target, leading to a greater antiplatelet effect. We conducted a systematic review of randomized controlled trials (RCTs) to determine the efficacy of once- versus twice-daily ASA in conditions with increased platelet turnover. METHODS: We conducted a systematic review and meta-analysis by searching the CENTRAL, MEDLINE, and Embase databases for RCTs assessing once- versus twice-daily ASA. Data were screened, extracted, and appraised by two independent reviewers, and were pooled using a random-effects model. The primary outcomes were major adverse cardiovascular events (MACEs) and serum thromboxane B2 (TxB2). Other pharmacodynamic measures were retrieved as secondary outcomes. Results were reported as mean differences with corresponding 95% confidence intervals (CIs). We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Seven RCTs were included, enrolling 379 participants overall. None of the studies reported clinical outcomes. Pooled results showed that compared with once-daily ASA, twice-daily ASA was associated with a decrease in mean TxB2 of 1.42 ng/mL (95% CI - 2.71 to - 0.13; I2 = 66%). We found no differences in subgroup analyses based on disease subtype, trial blinding, or trial design. A greater antiplatelet activity of the twice-daily regimen was also found when using PFA-100-ADP methods, although not when using the VerifyNow, LTA-AA, and multiplate methods. CONCLUSIONS: Twice-daily ASA was associated with a greater antiplatelet effect compared with standard once-daily ASA.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Trombose/prevenção & controle , Administração Oral , Anti-Inflamatórios não Esteroides/administração & dosagem , Aspirina/administração & dosagem , Esquema de Medicação , Humanos , Inibidores da Agregação Plaquetária/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Tromboxano B2/sangue
7.
Clin Pharmacol Ther ; 109(6): 1546-1554, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33141921

RESUMO

Dual antiplatelet therapy (DAPT) is standard in acute coronary syndrome but confers a bleeding risk. To compare effects of clopidogrel single antiplatelet therapy (SAPT) with clopidogrel-based DAPT on hemostatic system activation we conducted a randomized clinical trial in 44 volunteers (clopidogrel (d1: 600 mg, d2-6: 150 mg) ± aspirin (100 mg)). Multiple electrode aggregometry-adenosine diphosphate (MEA-ADP) and MEA-arachidonic acid (MEA-AA) triggered aggregometry, vasodilator-stimulated phosphoprotein (VASP), beta thromboglobulin, p-selectin, thromboxane B2 , d-Dimer, prothrombin fragment 1.2 (f1.2), and a phospholipid-dependent clotting time were measured in venous blood. Changes are described by mean differences (Δmean (95% confidence interval (CI)) or geometric mean ratios (95% CI)). DAPT and SAPT comparably and significantly decreased MEA-ADP at 2 hours (-60% vs. -63%; P = 0.35, Δmean -4.9, 95% CI -15.4 to 5.5). At 24 hours (-59% vs. -47%, P = 0.04, Δmean -11.1, 95% CI -21.7 to -0.4]) and 8 days (-61% vs. -53%, P = 0.04, Δmean -11.3, 95% CI -22.0 to -0.6). Both treatments significantly reduced VASP and MEA-AA after 2 hours and 8 days. DAPT inhibited MEA-AA significantly stronger at 2 hours (-77% vs. -30%; P < 0.0001, Δmean -39.6, 95% CI -54.2 to -25.0), at 24 hours (-80% vs. -27%, P < 0.0001, Δmean -47.8, 95% CI -62.3 to -33.3), and 8 days (-79% vs. -27%, P < 0.0001, Δmean -48.9, 95% CI -62.5 to -35.4). Neither treatment significantly influenced beta thromboglobulin or p-selectin. DAPT abolished and SAPT reduced thromboxane B2 after 24 hours and 8 days. The d-Dimer was reduced by DAPT (0.94, 95% CI 0.89-1.00, P = 0.04) at 2 hours but not after 24 hours and 8 days. SAPT did not decrease d-Dimer. Neither treatment affected f1.2. DAPT and SAPT comparably affect platelet and coagulation activation in venous blood.


Assuntos
Aspirina/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Clopidogrel/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Difosfato de Adenosina/metabolismo , Adulto , Ácido Araquidônico/metabolismo , Moléculas de Adesão Celular/metabolismo , Quimioterapia Combinada , Voluntários Saudáveis , Humanos , Masculino , Proteínas dos Microfilamentos/metabolismo , Selectina-P/sangue , Fosfoproteínas/metabolismo , Tromboxano B2/sangue , Tempo de Coagulação do Sangue Total , Adulto Jovem , beta-Tromboglobulina/metabolismo
8.
Vascul Pharmacol ; 136: 106819, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33207279

RESUMO

BACKGROUND: Recent data suggest a decreased clinical efficacy of low-dose aspirin in patients weighing ≥70 kg. We therefore investigated the impact of body weight and class 1 obesity on thromboxane generation and platelet reactivity to arachidonic acid (AA) in 316 patients on dual antiplatelet therapy following angioplasty and stenting. METHODS: Platelet surface expression of P-selectin and activated glycoprotein (GP) IIb/IIIa in response to AA were determined by flow cytometry as sensitive markers of platelet activation. Urinary 11-dehydro-thromboxane B2 (11-dehydro-TXB2) and serum TXB2 were measured by commercially-available immunoassays. On-treatment residual AA-inducible platelet aggregation was assessed by light transmission aggregometry (LTA), the VerifyNow aspirin assay and multiple electrode aggregometry (MEA). RESULTS: Class 1 obesity was independently associated with increased platelet surface expression of P-selectin and activated GPIIb/IIIa, but not with urinary 11-dehydro-TXB2, serum TXB2, and on-treatment platelet aggregation by all assays. Of all measured parameters, only MEA showed a positive albeit very weak correlation with body weight (r = 0.13, p = 0.02). Furthermore, the results of all tests did not differ significantly between patients without and with a body weight ≥ 70 kg. After adjustment for age and diabetes by multivariate logistic regression analysis, the frequency of high-on treatment residual TXB2 generation and high on-treatment residual AA-inducible platelet reactivity (HRTG/HRPR) did not differ significantly between obese and non-obese patients. CONCLUSION: Class 1 obesity is associated with enhanced platelet activation in response to AA in patients on dual antiplatelet therapy. This seems to be independent of cyclooxygenase-1 inhibition and does not translate into HRTG/HRPR.


Assuntos
Angioplastia , Aspirina/administração & dosagem , Plaquetas/efeitos dos fármacos , Doenças Cardiovasculares/terapia , Obesidade/complicações , Inibidores da Agregação Plaquetária/administração & dosagem , Agregação Plaquetária/efeitos dos fármacos , Idoso , Angioplastia/efeitos adversos , Angioplastia/instrumentação , Aspirina/efeitos adversos , Biomarcadores/sangue , Biomarcadores/urina , Plaquetas/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/diagnóstico , Terapia Antiplaquetária Dupla , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/diagnóstico , Selectina-P/sangue , Inibidores da Agregação Plaquetária/efeitos adversos , Testes de Função Plaquetária , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Stents , Tromboxano B2/análogos & derivados , Tromboxano B2/sangue , Tromboxano B2/urina , Fatores de Tempo , Resultado do Tratamento
9.
J Thromb Thrombolysis ; 51(2): 260-264, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33170486

RESUMO

Arachidonic acid (AA)-induced platelet aggregation (PA) and serum thromboxane B2 (TxB2) 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 TxB2 inhibition. We serially measured AA-PA (conventional aggregation), serum TxB2, plasma ASA and salicylic acid (SA) (liquid chromatography-mass spectrometry), and urinary 11-dehydro thromboxane B2 (u11-dh TxB2) (enzyme-linked 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 TxB2 (31-680 ng/mL) as compared to maximal AA-PA (65-81%) and u11-dh TxB2 (1556-4440 pg/mg creatinine). The relation between serum TxB2 inhibition and AA-PA was stepwise; after 30-40% inhibition of serum TxB2, 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 TxB2 inhibition and AA-PA. Aggregation was nil once TxB2 inhibition reached > 49%. Moreover, these results suggest that the definition of > 95% inhibition of serum TxB2 to indicate the level of platelet COX-1 inhibition needed for clinical efficacy may be overestimated and should be re-considered in future translational research investigations that attempt to link the clinical efficacy of ASA with a laboratory measurement cutoff.


Assuntos
Aspirina/farmacologia , Plaquetas/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Tromboxano B2/antagonistas & inibidores , Adulto , Aspirina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Projetos Piloto , Inibidores da Agregação Plaquetária/administração & dosagem , Tromboxano B2/sangue , Adulto Jovem
10.
Oxid Med Cell Longev ; 2020: 4165358, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194001

RESUMO

BACKGROUND: Although preclinical studies highlighted the potential role of NADPH oxidase (NOX) in sepsis, only few studies evaluated the oxidative stress in patients with sepsis and septic shock. The objective of the study is to appraise the oxidative stress status and platelet function in patients with sepsis and septic shock compared to healthy controls. METHODS AND RESULTS: Patients with sepsis or septic shock admitted to the hospital Policlinico Umberto I (Sapienza University, Rome) underwent a blood sample collection within 1 hour from admission. Platelet aggregation, serum thromboxane B2 (TxB2), soluble NOX2-derived peptides (sNox2-dp), and hydrogen peroxide breakdown activity (HBA) were measured and compared to those of healthy volunteers. Overall, 33 patients were enrolled; of these, 20 (60.6%) had sepsis and 13 (39.4%) septic shock. Compared to healthy controls (n = 10, age 67.8 ± 3.2, male 50%), patients with sepsis and septic shock had higher platelet aggregation (49% (IQR 45-55), 60% (55.75-67.25), and 73% (IQR 69-80), respectively, p < 0.001), higher serum TxB2 (77.5 (56.5-86.25), 122.5 (114-131.5), and 210 (195-230) pmol/L, respectively, p < 0.001), higher sNox2-dp (10 (7.75-12), 19.5 (17.25-21), and 33 (29.5-39) pg/mL, respectively, p < 0.001), and lower HBA (75% (67.25-81.5), 50% (45-54.75), and 27% (21.5-32.5), respectively, p < 0.001). Although not statistically significant, a trend in higher levels of serum TxB2 and sNox2-dp in patients who died was observed. CONCLUSIONS: Patients with septic shock exhibit higher Nox2 activity and platelet activation than patients with sepsis. These insights joined to better knowledge of these mechanisms could guide the identification of future prognostic biomarkers and new therapeutic strategies in the scenario of septic shock.


Assuntos
Plaquetas/enzimologia , NADPH Oxidase 2/sangue , Ativação Plaquetária , Choque Séptico/sangue , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Choque Séptico/mortalidade , Taxa de Sobrevida , Tromboxano B2/sangue
11.
Undersea Hyperb Med ; 47(4): 539-549, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33227829

RESUMO

Background: The popularity of apneic diving is continually growing. As apnea diving substantially burdens the cardiovascular system, special focus is warranted. Regarding inflammation processes and associated inflammatory-related diseases (e.g., cardiovascular diseases), eicosanoids play an important role. This study aims to investigate polyunsaturated fatty acids (PUFAs) and eicosanoids in voluntary apnea divers, and so to further improve understanding of pathophysiological processes focusing on proinflammatory effects of temporarily hypercapnic hypoxia.. Methods: The concentration of PUFAs and eicosanoids were investigated in EDTA plasma in apnea divers (n=10) before and immediately after apnea, 0.5 hour and four hours later, applying liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Mean age was 41±10 years, and divers performed a mean breath-hold time of 317±111 seconds. PUFAs, eicosanoids and related lipids could be classified in four different kinetical reaction groups following apnea. The first group (e.g., Ω-6 and Ω-3-PUFAs) showed an immediate concentration increase followed by a decrease below baseline four hours after apnea. The second group (e.g., thromboxane B2) showed a slower increase, with its maximum concentration 0.5 hour post-apnea followed by a decrease four hours post-apnea. Group 3 (9- and 13-hydroxyoctadecadienoic acid) is characterized by two concentration increase peaks directly after apnea and four hours afterward compared to baseline. Group 4 (e.g., prostaglandin D2) shows no clear response. Conclusion: Changes in the PUFA metabolism after even a single apnea revealed different kinetics of pro- and anti-inflammatory regulations and changes for oxidative stress levels. Due to the importance of these mediators, apnea diving should be evaluated carefully and be performed only with great caution against the background of cardiovascular diseases and inflammation processes.


Assuntos
Apneia/sangue , Suspensão da Respiração , Mergulho/fisiologia , Eicosanoides/sangue , Ácidos Graxos Insaturados/sangue , Adulto , Cromatografia Líquida/métodos , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-6/sangue , Feminino , Humanos , Ácidos Hidroxieicosatetraenoicos/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Prostaglandina D2/sangue , Espectrometria de Massas em Tandem/métodos , Tromboxano B2/sangue , Fatores de Tempo
12.
Neuro Endocrinol Lett ; 41(2): 102-106, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33185996

RESUMO

OBJECTIVE: The aim of our study was to establish whether or not tinnitus patients have higher platelet activity, as measured by plasma 11-dehydro-thromboxane B2 levels, compared with individuals without tinnitus. METHODS: The study group included patients without documented organic causes of tinnitus or a cause of non-vascular hearing impairment. Laboratory tests included complete blood count, biochemistry, coagulation activity, and thromboxane levels. To exclude a pathology in the cerebellopontine angle, CT and MRI were performed together with an X-ray scan of cervical vertebrae. For the purpose of this study, blood samples were screened for 11-dehydro-thromboxane B2 levels using commercial kits. RESULTS: A comparison of the main marker of increased platelet activity i.e., thromboxane levels of tinnitus patients with those of a control group, showed increased thromboxane levels in the former. The average plasma concentrations of 11-dehydro-thromboxane B2 were 2.0234±1.80 ng/ml in the group of tinnitus patients and 1.3247±1.33 ng/ml in the control group. Our results showed that patients with tinnitus have significantly higher values of 11-dehydro-thromboxane B2. CONCLUSION: Tinnitus patients showed higher levels of increased platelet activity, a marker that may play an important role in the pathogenesis of tinnitus.


Assuntos
Plaquetas/metabolismo , Tromboxano B2/análogos & derivados , Zumbido/sangue , Adulto , Coagulação Sanguínea , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Tromboxano B2/sangue
13.
BMC Nephrol ; 21(1): 394, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917166

RESUMO

BACKGROUND: Platelet activation is an important side effect of dialysis, resulted in a subsequent release of arachidonic acid (AA) from activated platelets. AA is involved in many pathologic conditions, such as inflammation, asthma, cancer, diabetes, hypertension, and the pathogenesis of kidney disease. The aim of this study was to define whether the dialysis type affects the concentration of AA derivatives in patients with chronic kidney disease. METHODS: 117 patients were qualified to the study group. Based on the type of renal replacement therapy, patients were divided into the following groups: hemodialysis (HD A - before/HD B - after hemodialysis), peritoneal dialysis (PD), kidney transplant patients (TE - before/TE A - after transplantation) and conservative treatment (CT) (30; 30; 27; 30 patients, respectively). The control group consisted of 30 healthy volunteers (NK). The ELISA methods were used to measure the concentrations of TXB2, 5-HETE, 12-HETE, and 15-HETE in the blood serum. RESULTS: Renal replacement therapy significantly influences the concentration of TXB2 (mean ± SD [ng/mL]: HD A- 34.6 ± 9; HD B- 28.3 ± 15.2; PD- 28.3 ± 15.2; CT- 34.2 ± 8.0; TE- 36.7 ± 42.9; TE A- 27.9 ± 8.8; NK- 19.6 ± 15; p = 0.010), 5-HETE (mean ± SD [ng/mL]: HD A- 284.2 ± 428.4; HD B- 304.8 ± 516.2; PD - 530.0 ± 553.3; CT- 318.7 ± 366.0; TE- 525.6 ± 358.0; TE A - 409.8 ± 377.1; NK 838.1 ± 497.8; p < 0.001) and 15-HETE (HD A-18.1 ± 8.7; HD B- 42.2 ± 14; PD - 36.3 ± 13.8; CT- 33.7 ± 14.0; TE- 19.5 ± 10.2; TE A - 34.4 ± 16.3; NK 22.2 ± 17.8; p < 0,001). There was a significant relationship between the type of renal replacement therapy and the duration of dialysis, and the concentration of TXB2, 12-HETE acid, and 15-HETE. CONCLUSIONS: The type of renal replacement therapy significantly affects the concentration of AA derivatives. Peritoneal dialysis is the best method of dialysis, taking into account the concentration of arachidonic acid derivatives.


Assuntos
Ácido Araquidônico/sangue , Ácidos Hidroxieicosatetraenoicos/sangue , Falência Renal Crônica/sangue , Terapia de Substituição Renal/métodos , Tromboxano B2/sangue , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/sangue , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Tratamento Conservador/métodos , Feminino , Humanos , Falência Renal Crônica/terapia , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Diálise Peritoneal/métodos , Diálise Renal/métodos
15.
Mol Nutr Food Res ; 64(19): e2000694, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32844550

RESUMO

SCOPE: The aim of this study is to examine whether postprandial (PP) triglyceride-rich lipoproteins (TGRL) secreted after a moderate fat intake would activate platelets differently according to their fatty acid (FA) composition. METHODS AND RESULTS: In a parallel single-blind randomized trial, 30 women with type 2 diabetes are assigned a breakfast containing 20 g lipids from butter versus hazelnut-cocoa spread (HCS) rich in palm oil. Blood samples are collected at fasting and 4 h PP. FA composition of fasting and PP TGRL and their effects on the activation of platelets from healthy blood donors are assessed. Both breakfasts similarly increase plasma ApoB-48, plasma, and TGRL triglycerides (p < 0.05). TGRL mean diameter increases after both breakfasts and is greater after the butter breakfast. Both breakfasts are rich in palmitic acid, and the HCS breakfast contains 45% oleic acid. TGRL FA composition reflects the dietary FA composition. Pre-incubation of platelets with fasting and PP TGRL increases collagen-stimulated aggregation (p < 0.01 vs control). Fasting and PP TGRL similarly increase agonist-induced thromboxane B2 concentrations, and this effect is concentration-dependent for PP TGRL. CONCLUSION: PP TGRL from type 2 diabetic women after a palm-oil spread versus butter-based mixed meal induce similar acute in vitro platelet activation.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Gorduras na Dieta/farmacologia , Lipoproteínas/sangue , Refeições , Ativação Plaquetária/fisiologia , Idoso , Idoso de 80 Anos ou mais , Laticínios , Jejum , Feminino , Humanos , Lipoproteínas/química , Pessoa de Meia-Idade , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária , Período Pós-Prandial , Tromboxano B2/sangue , Triglicerídeos/sangue
16.
Thromb Haemost ; 120(10): 1442-1453, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32717754

RESUMO

Essential thrombocythemia (ET) patients are treated with aspirin (acetylsalicylic acid [ASA]) to prevent thrombosis. Previous studies showed that serum thromboxane (Tx) B2 was high 24 hours after enteric-coated (EC)-ASA in ET patients, due to increased number of noninhibited reticulated platelets (RPs), consequent to high platelet turnover, and that ASA should be given twice a day to ET patients. We studied ET patients (n = 17) and healthy subjects (n = 10) on 100 mg EC-ASA once daily; experiments were repeated after 14-day treatment with 100 mg plain-ASA once daily. Serum TxB2, plasma ASA, and salicylic acid (SA) were measured before the morning dose and up to 8 hours thereafter. Blood activity of ASA-deacethylating esterases, in vitro inhibition of collagen-induced TxB2 production by ASA (10-1,000 µM), and number of RP were measured. TxB2 inhibition by ASA in vitro and esterases activities were normal in all subjects. EC-ASA elicited highly variable responses; 6 ET patients were poor responders, as their serum TxB2 was high after EC-ASA; their plasma levels of ASA and SA were low/undetectable. In contrast to EC-ASA, plain ASA decreased serum TxB2 and increased plasma ASA and SA in all subjects. Serum TxB2 was high in ET patients at 24 hours and significantly correlated with RP count (but not RP percentage) and platelet count. Plain ASA should be used in ET patients to inhibit platelets efficiently. The identification of ET patients who might benefit from twice a day ASA could simply be based on their platelet count: since their platelet turnover is not increased, ET patients with normalized platelet count should not need twice a day ASA treatment.


Assuntos
Aspirina/uso terapêutico , Fibrinolíticos/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Trombocitemia Essencial/tratamento farmacológico , Trombose/prevenção & controle , Idoso , Aspirina/farmacocinética , Plaquetas/efeitos dos fármacos , Feminino , Fibrinolíticos/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/farmacocinética , Comprimidos com Revestimento Entérico , Trombocitemia Essencial/sangue , Trombocitemia Essencial/complicações , Trombose/sangue , Trombose/etiologia , Tromboxano B2/sangue , Resultado do Tratamento
17.
Biosci Rep ; 40(6)2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32441737

RESUMO

BACKGROUND: The present study was designed to explore the regulatory mechanisms and influences of cotinine on deep vein thrombosis (DVT) in rats via the toll-like receptor 4/nuclear factor κ binding (TLR-4/NF-κB) pathway. METHODS: In this experimental study, 30 SD rats were randomly assigned to control group, sham operation group, model group, cotinine (10 µg/kg) group, and model + cotinine (10 µg/kg) group. The thromboxane B2 (TXB2), 6-keto-PGF1α, plasminogen activator inhibitor (PAI), tissue plasminogen activator (t-PA), TLR4, NF-κB, and p65 mRNA and protein expression and tissue changes were analyzed by ELISA, Hematoxylin-Eosin (HE) staining, RT-PCR, and Western blot. RESULTS: There was no significant difference between the control and sham operation groups (P>0.05). The model and cotinine groups showed significantly higher mRNA and protein levels of TXB2, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), PAI, TLR-4, and NF-κB, and significantly lower levels of 6-keto-PGF1α and t-PA than the control and sham operation groups (P<0.05), and the model + cotinine group showed significantly higher mRNA and protein levels of TXB2, IL-6 and TNF-α, PAI, TLR-4, and NF-κB and significantly lower levels of 6-keto-PGF1α and t-PA than the model group (P<0.05). CONCLUSION: Cotinine can aggravate thrombus and inflammation in rats with DVT, and the mechanism may be associated with the activation of the TLR-4/NF-κB inflammatory signaling pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Cotinina/farmacologia , Fibrinolíticos/farmacologia , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Trombose Venosa/tratamento farmacológico , 6-Cetoprostaglandina F1 alfa/sangue , Animais , Modelos Animais de Doenças , Masculino , NF-kappa B/genética , Ratos Sprague-Dawley , Transdução de Sinais , Tromboxano B2/sangue , Receptor 4 Toll-Like/genética , Trombose Venosa/genética , Trombose Venosa/metabolismo
18.
Medicine (Baltimore) ; 99(20): e20307, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443379

RESUMO

INTRODUCTION: Uncertainty remains regarding the impact of enteric-coated (EC) aspirin as it relates to the reduction of cardiovascular risk. We hypothesize that EC formulation based on a previous report may blunt aspirin response as evidenced by reduced Thromboxane A2 (TXA 2) levels in diabetic patients. Thus, it was imperative to ascertain and validate the effect of the EC formulation of Aspirin on the Thromboxane B2 (TXB2) level. METHODS/DESIGN: An open-label consecutive randomized interventional controlled trial. Patients with newly diagnosed ischemic stroke who are just about to start Aspirin were assessed for eligibility and inclusion in our trial. Consecutive patients (admitted to the stroke unit of Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar) will be randomized to receive either EC aspirin or plain Aspirin. They will be required to continue taking them throughout the study (3 days). Demographics and laboratory records of the study participants will be abstracted from online records. Further study variables will be obtained manually in designated case record forms (CRF). The primary outcomes are the incidence of aspirin non-responders (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). Whereas secondary outcomes are the incidence of GIT bleeding of various preparations of Aspirin. The study was approved by MRC and IRB of Hamad Medical Corporation (MRC number: 01-18-156). DISCUSSION: This trial will determine potential differences in the efficacy of EC Aspirin and plain Aspirin on the Thromboxane B2 level. Additionally, it will ascertain the tolerability and safety of both formulations of Aspirin in patients with newly diagnosed ischemic stroke. These results will either support the current notion of no difference between the two formulations. However, if a difference is found, this will invite for future trials exploring clinical outcomes occurrence between various formulations. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT04330872 registered on April 2, 2020.


Assuntos
Aspirina/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Adolescente , Adulto , Idoso , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Plaquetas/efeitos dos fármacos , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/efeitos adversos , Método Simples-Cego , Fatores Socioeconômicos , Comprimidos com Revestimento Entérico , Tromboxano B2/sangue , Adulto Jovem
19.
Nutrients ; 12(5)2020 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-32456230

RESUMO

Chronic hyperglycemia increases oxidative stress, activates inflammatory pathways and reduces nerve growth factor (NGF) among diabetic patients, which contribute to development of diabetic peripheral neuropathy (DPN). Tocotrienol-Rich Vitamin E (Tocovid) possesses potent antioxidant and anti-inflammatory properties which are postulated to target these pathogeneses in order to ameliorate DPN. This study aims to evaluate the effects of Tocovid on nerve conduction parameters and serum biomarkers among diabetic patients. This multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial was conducted on 80 eligible participants. The intervention group (n = 39) was randomly allocated to receive 200 mg of Tocovid twice a day, and the control group (n = 41) received placebo twice a day. At the end of eight weeks, the nerve conduction parameters, as assessed by nerve conduction study, as well as serum biomarkers (NGF, malondialdehyde, vascular cell adhesion molecule 1, tumor necrosis factor receptor 1 and thromboxane B2) were compared between the two groups. Compared to placebo, Tocovid significantly improves the nerve conduction velocities of all nerves (+1.25 m/s, interquartile range [IQR] 3.35, p < 0.001, median nerve; +1.60 m/s, IQR 1.80, p < 0.001, sural nerve; +0.75 m/s, IQR 2.25, p < 0.001, tibial nerve). Meanwhile, the levels of serum NGF were significantly higher in the Tocovid group as compared to placebo at eight weeks post-intervention. Participants receiving Tocovid illustrated highly significant improvement in terms of nerve conduction velocities for all nerves tested after eight weeks of supplementation. In addition, Tocovid supplementation elevated the levels of serum NGF, in which its increase is postulated to reflect enhanced neuronal functions. This novel finding suggests that Tocovid could be a disease-modifying agent targeting serum NGF to improve nerve conduction velocities.


Assuntos
Neuropatias Diabéticas/tratamento farmacológico , Tocotrienóis/uso terapêutico , Vitamina E/uso terapêutico , Idoso , Antioxidantes/uso terapêutico , Biomarcadores/sangue , Neuropatias Diabéticas/sangue , Método Duplo-Cego , Feminino , Seguimentos , Taxa de Filtração Glomerular , Hemoglobina A Glicada/metabolismo , Humanos , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Fator de Crescimento Neural/sangue , Condução Nervosa/efeitos dos fármacos , Cooperação do Paciente , Estudos Prospectivos , Receptores do Fator de Necrose Tumoral/sangue , Tromboxano B2/sangue , Tocotrienóis/farmacologia , Molécula 1 de Adesão de Célula Vascular/sangue
20.
Arterioscler Thromb Vasc Biol ; 40(5): 1340-1351, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32131611

RESUMO

OBJECTIVE: Patients with psoriasis have impaired vascular health and increased cardiovascular disease (CVD). Platelets are key players in the pathogenesis of vascular dysfunction in cardiovascular disease and represent therapeutic targets in cardiovascular prevention. The object of this study was to define the platelet phenotype and effector cell properties on vascular health in psoriasis and evaluate whether aspirin modulates the platelet-induced phenotype. Approach and Results: Platelets from psoriasis patients (n=45) exhibited increased platelet activation (relative to age- and gender-matched controls, n=18), which correlated with psoriasis skin severity. Isolated platelets from psoriasis patients demonstrated a 2- to 3-fold (P<0.01) increased adhesion to human aortic endothelial cells and induced proinflammatory transcriptional changes, including upregulation of IL 8 (interleukin 8), IL1ß, and Cox (cyclooxygenase)-2 Platelet RNA sequencing revealed an interferon signature and elevated expression of COX-1, which correlated with psoriasis disease severity (r=0.83, P=0.01). In a randomized trial of patients with psoriasis, 2 weeks of 81 mg low-dose aspirin, a COX-1 inhibitor, reduced serum thromboxane (Tx) B2 and reduced brachial vein endothelial proinflammatory transcript expression >70% compared with the no-treatment group (P<0.01). Improvement in brachial vein endothelial cell inflammation significantly correlated with change in serum TxB2 (r=0.48, P=0.02). CONCLUSIONS: In patients with psoriasis, platelets are activated and induce endothelial cell inflammation. Low-dose aspirin improved endothelial cell health in psoriasis via platelet COX-1 inhibition. These data demonstrate a previously unappreciated role of platelets in psoriasis and endothelial cell inflammation and suggests that aspirin may be effective in improving vascular health in patients with psoriasis. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03228017.


Assuntos
Plaquetas/enzimologia , Ciclo-Oxigenase 1/sangue , Células Endoteliais/enzimologia , Ativação Plaquetária , Psoríase/sangue , Adulto , Aspirina/administração & dosagem , Plaquetas/efeitos dos fármacos , Células Cultivadas , Ciclo-Oxigenase 1/genética , Inibidores de Ciclo-Oxigenase/administração & dosagem , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adesividade Plaquetária , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Psoríase/enzimologia , Índice de Gravidade de Doença , Transdução de Sinais , Tromboxano B2/sangue , Resultado do Tratamento
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