Assuntos
Plaquetas/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Inibidores da Agregação Plaquetária/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y12/sangue , Insuficiência Renal Crônica/sangue , Ticlopidina/análogos & derivados , Biomarcadores/sangue , Plaquetas/metabolismo , Moléculas de Adesão Celular/sangue , Clopidogrel , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Relação Dose-Resposta a Droga , Resistência a Medicamentos , Humanos , Proteínas dos Microfilamentos/sangue , Fosfoproteínas/sangue , Estudos Prospectivos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Transdução de Sinais/efeitos dos fármacos , Ticlopidina/farmacologiaRESUMO
Several platelet function tests (PFT) are available to assess the pharmacodynamic (PD) effects of P2Y12 inhibitors. However, there are technical variances between PFT, and P2Y12 inhibitors differ in pharmacological properties. Manufactures of PFT recommend a time-frame within which assessments needs to be executed. However, if the timing from blood sampling to processing affects PD results is unknown. We conducted a prospective study assessing the impact of timing from blood sampling to processing on PD measures using three different PFT. We studied 60 aspirin-treated patients with coronary artery disease (CAD) on maintenance P2Y12 inhibiting therapy [clopidogrel 75 mg/day (n=20), prasugrel 10 mg/day (n=20) and ticagrelor 90 mg bid (n=20)]. PD assessments (trough levels) were performed by VerifyNow P2Y12 (VN), light transmittance aggregometry (LTA) and vasodilator-stimulated phosphoprotein (VASP) at 30 minutes, 2 and 4 hours post-sampling; VASP was also performed at 24 hours. P2Y12 reaction units (PRU) by VN significantly decreased over time with all P2Y12 inhibitors (clopidogrel p<0.001; prasugrel p=0.016; ticagrelor p<0.001). PRU at 30 minutes and 2 hours were similar, but decreased at 4 hours. LTA showed consistent findings with VN. Conversely, PD measures as assessed by VASP were stable over time (p>0.1 for all P2Y12 inhibitors). In conclusion, in CAD patients on maintenance therapy with P2Y12 inhibitors, timing from blood sampling to processing significantly influences PD measures as assessed by VN and LTA, but not by VASP.
Assuntos
Plaquetas/efeitos dos fármacos , Testes de Função Plaquetária , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Fatores de Tempo , Adenosina/análogos & derivados , Adenosina/uso terapêutico , Adulto , Moléculas de Adesão Celular , Estudos Transversais , Feminino , Humanos , Masculino , Proteínas dos Microfilamentos , Pessoa de Meia-Idade , Fosfoproteínas , Agregação Plaquetária , Inibidores da Agregação Plaquetária , Cloridrato de Prasugrel/uso terapêutico , Estudos Prospectivos , Ticagrelor , Ticlopidina/uso terapêuticoRESUMO
AIMS: Pharmacodynamic (PD) studies comparing prasugrel and ticagrelor have reached inconsistent findings. Therefore, a comprehensive investigation comparing the PD effects of prasugrel vs. ticagrelor after switching from clopidogrel therapy, exploring both loading dose (LD) and maintenance dose (MD) regimens represented the aim of this study. METHODS AND RESULTS: Patients (n = 110) with coronary artery disease were randomized to prasugrel (60 mg LD/10 mg MD q.d.) or ticagrelor (180 mg LD/90 mg MD b.i.d) therapy for 1 week. Pharmacodynamic assessments were conducted using three assays (vasodilator-stimulated phosphoprotein, VerifyNow P2Y12, and light transmittance aggregometry, LTA) at baseline, 30 min, 2, 24 h, and 1 week. The impact of initiating ticagrelor MD 12 vs. 24 h after LD administration was also assessed. Switching clopidogrel-treated patients to an LD of prasugrel or ticagrelor was associated with a reduction in platelet reactivity at 30 min and was sustained at all time points up to 1 week with the MD (P < 0.001 for all assays). Platelet reactivity was similar with prasugrel and ticagrelor with all assays at 30 min, 2 h, and 1 week (P > 0.05 for all time points), with the exception of LTA at 30 min (lower with prasugrel; P = 0.003). At 24 h, platelet reactivity was lower among patients initiating ticagrelor MD after 12 vs. 24 h post-LD. Rates of high platelet reactivity (HPR) were markedly reduced and similar between groups. CONCLUSION: Prasugrel and ticagrelor exert similar levels of P2Y12 inhibition achieving more potent PD effects and reduced HPR rates compared with clopidogrel which are reached promptly following LD and sustained with MD. CLINICALTRIALSGOV IDENTIFIER: NCT01852175.
Assuntos
Doença da Artéria Coronariana , Adenosina/análogos & derivados , Plaquetas , Clopidogrel , Humanos , Inibidores da Agregação Plaquetária , Testes de Função Plaquetária , Cloridrato de Prasugrel , Estudos Prospectivos , Ticagrelor , Ticlopidina/análogos & derivadosRESUMO
OBJECTIVES: The goal of this study was to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of escalating ticagrelor loading dose (LD) regimens in primary percutaneous coronary intervention (PPCI). BACKGROUND: Patients with ST-segment elevation myocardial infarction undergoing PPCI frequently have suboptimal platelet inhibition in the early hours after ticagrelor LD. The use of high ticagrelor LD regimens has been hypothesized to optimize platelet inhibition in PPCI. METHODS: This was a prospective, randomized study of escalating ticagrelor LD regimens (180 mg, 270 mg, or 360 mg) in PPCI (N = 52). PK/PD analyses were performed before and 30 min, 1, 2, 4, 8, and 24 h post-LD. PK assessments included exposure to ticagrelor and its metabolite (AR-C124910XX). PD assessments included P2Y12 reaction units (PRU) measured by VerifyNow P2Y12 and platelet reactivity index (PRI) measured by vasodilator-stimulated phosphoprotein (VASP). RESULTS: Platelet reactivity was elevated during the first 2 h post-LD. There were no differences in PRU between groups during the study time course (p = 0.179). There were no significant differences in PRU levels across groups at all time points, except at 1 h (p = 0.017) where platelet reactivity was lowest with a 270-mg LD. No differences were found between the 180-mg and 360-mg groups (primary endpoint; p > 0.999). High on-treatment platelet reactivity rates were not different across groups, except at 1 hour (p = 0.038). Parallel PD findings were observed with VASP-PRI. PK analysis showed a delay in ticagrelor absorption and generation of AR-C124910XX, irrespective of dose. Although morphine was associated with a delay in ticagrelor PK/PD, it was not an independent predictor of high on-treatment platelet reactivity. CONCLUSIONS: ST-segment elevation myocardial infarction patients undergoing PPCI frequently exhibit impaired response to ticagrelor in the early hours after drug administration, which cannot be overcome by increasing LD regimens. These PD findings are largely attributed to an impaired PK profile, indicating a delay in drug absorption compared with that reported in stable clinical settings. (High Ticagrelor Loading Dose in STEMI; NCT01898442).
Assuntos
Adenosina/análogos & derivados , Plaquetas/efeitos dos fármacos , Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Adenosina/administração & dosagem , Adenosina/efeitos adversos , Adenosina/farmacocinética , Idoso , Biotransformação , Plaquetas/metabolismo , Moléculas de Adesão Celular/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Absorção Intestinal , Masculino , Proteínas dos Microfilamentos/sangue , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Intervenção Coronária Percutânea/efeitos adversos , Fosfoproteínas/sangue , Inibidores da Agregação Plaquetária/efeitos adversos , Testes de Função Plaquetária , Estudos Prospectivos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Receptores Purinérgicos P2Y12/sangue , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Ticagrelor , Resultado do TratamentoRESUMO
OBJECTIVES: The aim of this study was to assess the impact of ticagrelor dosing regimens on pharmacodynamic (PD) profiles in patients on maintenance ticagrelor therapy. BACKGROUND: Many patients on maintenance P2Y12-inhibiting therapies may require coronary revascularization procedures, raising a common clinical question with regard to the dosing regimen of the P2Y12-inhibiting agent to be used. To date, investigations assessing dosing regimens of P2Y12 receptor inhibitors in patients on maintenance therapy have been only assessed with thienopyridines, but not with ticagrelor. METHODS: This was a prospective, randomized, double-blind, placebo-controlled study assessing the PD effects of 2 dosing regimens of ticagrelor in patients on standard aspirin and ticagrelor maintenance therapy. A total of 60 patients were randomized to either 90 mg (maintenance dose [MD] group) or 180 mg (loading dose [LD] group) dose of ticagrelor. PD assessments were conducted at 3 time points (baseline, 1 h and 4 h). PD assessments were defined according to the platelet reactivity index (PRI) (vasodilator-stimulated phosphoprotein phosphorylation assay), P2Y12 reaction unit (VerifyNow P2Y12 assay) and adenosine diphosphate-induced platelet aggregation by light transmittance aggregometry. RESULTS: There were no differences in baseline levels of platelet reactivity with all assays. Intergroup comparisons by means of repeated-measures analysis adjusted for baseline PRI values showed that the LD group had significantly lower PRI levels compared with the MD group during the overall study time course (p = 0.031). Consistent findings were found for P2Y12 reaction unit (p = 0.026) and light transmittance aggregometry (p = 0.004). Intragroup comparisons showed that a more prompt and sustained platelet inhibitory effect was achieved more consistently with an LD regimen compared with a MD regimen. CONCLUSIONS: In patients on maintenance ticagrelor therapy, a 180-mg LD regimen of ticagrelor is associated with more potent and prompt platelet inhibition compared with a 90-mg MD. (Impact of Ticagrelor Re-Load Pharmacodynamic Profiles; NCT01731041).
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Adenosina/análogos & derivados , Plaquetas/efeitos dos fármacos , Inibidores da Agregação Plaquetária/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Adenosina/administração & dosagem , Adenosina/efeitos adversos , Idoso , Biomarcadores/sangue , Plaquetas/metabolismo , Moléculas de Adesão Celular/sangue , Método Duplo-Cego , Esquema de Medicação , Feminino , Florida , Humanos , Masculino , Proteínas dos Microfilamentos/sangue , Pessoa de Meia-Idade , Fosfoproteínas/sangue , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/efeitos adversos , Testes de Função Plaquetária , Estudos Prospectivos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Receptores Purinérgicos P2Y12/sangue , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Ticagrelor , Fatores de Tempo , Resultado do TratamentoRESUMO
Platelet activation with subsequent aggregation is a complex process leading to thrombus formation, which remains a key component for atherothrombotic manifestations, in particular myocardial infarction. Therefore, antiplatelet therapies are pivotal for the treatment of these patients. Current oral antiplatelet therapies used for secondary prevention of ischemic recurrences include aspirin and adenosine diphosphate P2Y12 platelet-receptor antagonists. However, despite these therapies, patients who have experienced a myocardial infarction remain at risk for ischemic recurrences. Therefore, more aggressive secondary prevention measures have been an area of research, including identifying additional targets modulating platelet-activation and -aggregation processes. Among these, thrombin-mediated platelet activation via protease-activated receptors (PARs) has been subject to extensive clinical investigation. Several PAR-1 receptor antagonists have been developed. However, vorapaxar is the only one that has completed large-scale clinical investigation. The present manuscript will provide an overview on the role of thrombin-mediated signaling, the impact of PAR-1 blockade with vorapaxar on ischemic and bleeding outcomes, and the potential role for vorapaxar in clinical practice.
Assuntos
Plaquetas/efeitos dos fármacos , Lactonas/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Piridinas/uso terapêutico , Receptor PAR-1/antagonistas & inibidores , Animais , Plaquetas/enzimologia , Hemorragia/induzido quimicamente , Humanos , Lactonas/efeitos adversos , Lactonas/farmacocinética , Terapia de Alvo Molecular , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/enzimologia , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/farmacocinética , Piridinas/efeitos adversos , Piridinas/farmacocinética , Receptor PAR-1/sangue , Fatores de Risco , Prevenção Secundária , Transdução de Sinais/efeitos dos fármacos , Resultado do TratamentoRESUMO
Smokers have a greater relative benefit of clopidogrel therapy compared with nonsmokers, likely attributed to its enhanced pharmacodynamic (PD) effects. However, to date, all PD studies have been conducted in patients on dual antiplatelet therapy with aspirin and clopidogrel, and it is unknown whether clopidogrel monotherapy can offer more effective antithrombotic effects compared with aspirin alone among smoking patients. Sixty aspirin-treated (81 mg/day) patients with vascular disease, classified as nonsmokers, light smokers, and heavy smokers according to cotinine serum levels, were enrolled. Patients were switched to clopidogrel (75 mg/day) monotherapy for 7-10 days. PD assessments were performed before and after switch by multiple electrode aggregometry (MEA) and kaolin-activated thromboelastography (TEG). Complete PD data were obtained in 57 patients (nonsmokers, n = 27; light smokers, n = 13; heavy smokers, n = 17). On treatment platelet reactivity following MEA, adenosine diphosphate (ADP) + prostaglandin E1 (PGE1) and thrombin receptor-activating peptide (TRAP) stimuli were significantly lower among heavy smokers following switch to clopidogrel. A significant inverse effect was observed with MEA arachidonic acid (ASPI), while neutral findings were shown with MEA collagen (COLL) stimulus. Thrombin and fibrin activity assessed by clot generation parameters were all nonsignificantly different but showed trends towards enhanced antithrombotic activity with clopidogrel among heavy smokers. In heavy smokers with vascular disease manifestations, clopidogrel is associated with enhanced platelet inhibitory effects, affecting purinergic and non-purinergic pathways, compared with aspirin as measured by MEA. Moreover, among smokers, clopidogrel offers trends towards enhanced effects on parameters of clot generation measured by TEG.
Assuntos
Aspirina/uso terapêutico , Aterosclerose/tratamento farmacológico , Plaquetas/efeitos dos fármacos , Fibrinolíticos/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Fumar/sangue , Trombose/prevenção & controle , Ticlopidina/análogos & derivados , Adulto , Idoso , Aterosclerose/sangue , Aterosclerose/diagnóstico , Biomarcadores/sangue , Plaquetas/metabolismo , Clopidogrel , Cotinina/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Agregação Plaquetária/efeitos dos fármacos , Testes de Função Plaquetária , Estudos Prospectivos , Transdução de Sinais/efeitos dos fármacos , Fumar/efeitos adversos , Tromboelastografia , Trombose/sangue , Trombose/diagnóstico , Ticlopidina/uso terapêutico , Fatores de Tempo , Resultado do TratamentoRESUMO
Smoking enhances the P2Y12 receptor inhibitory effects of clopidogrel. Nicotine increases P2Y12 receptor expression in platelet lysates from healthy volunteers. However, the impact of cigarette smoking on platelet P2Y12 receptor binding in clopidogrel-treated patients with coronary artery disease (CAD) is unknown. Clopidogrel-naïve patients with stable CAD (n = 20) were enrolled and stratified according to smoking status. P2Y12 receptor binding activity was determined by radioligand receptor binding prior and 24 h after a 600-mg loading dose of clopidogrel. Baseline P2Y12 receptor binding was 1.8-fold higher in smokers compared with nonsmokers. After a 600-mg loading dose of clopidogrel, smokers showed a 6.4-fold reduction in P2Y12 receptor binding indicative of marked clopidogrel-mediated blockade, while there were minimal changes among nonsmokers. Among patients with stable CAD, smokers have more P2Y12 receptor binding than nonsmokers and have a higher degree of clopidogrel-mediated platelet inhibition.
Assuntos
Plaquetas/efeitos dos fármacos , Doença da Artéria Coronariana/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Fumar/sangue , Ticlopidina/análogos & derivados , Idoso , Plaquetas/metabolismo , Clopidogrel , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Inibidores da Agregação Plaquetária/sangue , Ensaio Radioligante , Receptores Purinérgicos P2Y12/metabolismo , Fumar/efeitos adversos , Ticlopidina/sangue , Ticlopidina/uso terapêutico , Resultado do TratamentoRESUMO
Platelets critically contribute to atherothrombosis and worsening ischaemia in patients with peripheral arterial disease (PAD), eventually leading to critical limb ischaemia (CLI). Furthermore, persistent platelet activation despite antiplatelet therapy has been reported in this setting. The prostacyclin analogue iloprost is currently recommended in CLI patients for its effects in relieving symptoms by promoting local perfusion. In this study, we investigated the effects of iloprost infusion on urinary 11-dehydro-TXB2 and 8-iso-PGF(2α) excretion rate, as in vivo indexes of thromboxane-dependent platelet activation and lipid peroxidation, respectively, and on platelet-derived proinflammatory sCD40L and nitric oxide bioavailability in 44 patients with CLI while on chronic treatment with low-dose aspirin. Daily iloprost infusion for one-week significantly decreased urinary 11-dehydro-TXB2 [499 (277-807) vs. 380 (189-560) pg/mg creatinine, p < 0.0001] and 8-iso-PGF(2α) [533 (316-842) vs. 334 (196-540) pg/mg creatinine, p < 0.0001] as well as plasma sCD40L [1540 (1005-3015) vs. 948 (845-2030) pg/ml, p < 0.0001]. Furthermore, a significant increase in plasma nitrate plus nitrite levels has been observed [26.8 (18.8-35.9) vs. 43.7 (33.0-75.5) µM, p < 0.0001]. A significant direct correlation was also found between urinary 8-iso-PGF(2α) and 11-dehydro-TXB2 before and after iloprost treatment (Rho = 0.695, p < 0.0001). In conclusion, we report that a short-term course of iloprost is able to significantly reduce residual thromboxane biosynthesis, oxidative stress, endothelial dysfunction and platelet-derived inflammation in low-dose aspirin treated patients with CLI.
Assuntos
Aspirina/uso terapêutico , Plaquetas/efeitos dos fármacos , Iloprosta/uso terapêutico , Mediadores da Inflamação/sangue , Isquemia/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Biomarcadores/urina , Plaquetas/imunologia , Ligante de CD40/sangue , Distribuição de Qui-Quadrado , Estado Terminal , Dinoprosta/análogos & derivados , Dinoprosta/urina , Esquema de Medicação , Feminino , Humanos , Iloprosta/administração & dosagem , Infusões Intravenosas , Isquemia/sangue , Isquemia/imunologia , Isquemia/urina , Itália , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/sangue , Inibidores da Agregação Plaquetária/administração & dosagem , Tromboxano B2/análogos & derivados , Tromboxano B2/urina , Fatores de Tempo , Resultado do TratamentoRESUMO
Thromboxane (TX) biosynthesis by platelets and other cells in response to inflammatory triggers may provide a link between chronic inflammatory disease and atherothrombosis in rheumatoid arthritis (RA). In this study, we investigated the determinants of TX biosynthesis in RA, with particular reference to enhanced oxidative stress, receptor for advanced glycation end-products (RAGE) hyperactivity, and anti-tumor necrosis factor (TNF) treatment. Fifty-four patients with RA and 20 healthy subjects were recruited and a cross-sectional comparison of urinary 11-dehydro-TXB(2), 8-iso-PGF(2alpha), and plasma endogenous secretory RAGE (esRAGE) levels was performed between patients and controls. Urinary 11-dehydro-TXB(2) was significantly higher in RA patients than in healthy controls [425 (309-592) vs 233 (158-327) pg/mg creatinine, P<0.0001]. Furthermore, urinary 8-iso-PGF(2alpha) [323 (221-515) vs 172 (91-292) pg/mg creatinine, P<0.0001] and plasma esRAGE [155 (100-240) vs 377 (195-486) pg/ml, P=0.001] were higher and lower, respectively, in patients than in controls. A direct correlation was found between urinary 11-dehydro-TXB(2) and 8-iso-PGF(2alpha) only in patients not on anti-TNF therapy (r=0.420, P=0.021). Conversely, patients on anti-TNF therapy showed significantly lower urinary 8-iso-PGF(2alpha) [284 (201-373) vs 404 (241-539) pg/mg creatinine, P=0.043] but not 11-dehydro-TXB(2) than anti-TNF-treated subjects, with esRAGE as the only independent predictor of 11-dehydro-TXB(2) in this group of patients (adjusted R(2)=0.496, beta=-0.725, SEM=0.025, P=0.001). In conclusion, we provide biochemical evidence of enhanced TX biosynthesis in patients with RA, driven, at least in part, by lipid peroxidation. Treatment with anti-TNF agents may blunt isoprostane generation in the absence of significant effects on TX biosynthesis. We suggest that RAGE hyperactivity may escape TNF blockade, thus contributing to persistent TX biosynthesis in this setting.
Assuntos
Artrite Reumatoide/metabolismo , Estresse Oxidativo/fisiologia , Receptores Imunológicos/fisiologia , Tromboxanos/biossíntese , Adulto , Idoso , Artrite Reumatoide/urina , Biomarcadores/análise , Estudos de Casos e Controles , Dinoprosta/análogos & derivados , Dinoprosta/urina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxidantes/farmacologia , Receptor para Produtos Finais de Glicação Avançada , Tromboxano B2/análogos & derivados , Tromboxano B2/urinaRESUMO
We tested whether cyclooxygenase 2 (COX-2) expression and unacetylated COX-1 in newly formed platelets might contribute to persistent thromboxane (TX) biosynthesis in aspirin-treated essential thrombocythemia (ET). Forty-one patients on chronic aspirin (100 mg/day) and 24 healthy subjects were studied. Platelet COX-2 expression was significantly increased in patients and correlated with thiazole orange-positive platelets (r = 0.71, P < .001). The rate of TXA(2) biosynthesis in vivo, as reflected by urinary 11-dehydro-TXB(2) (TXM) excretion, and the maximal biosynthetic capacity of platelets, as reflected by serum TXB(2), were higher in patients compared with aspirin-treated healthy volunteers. Serum TXB(2) was significantly reduced by the selective COX-2 inhibitor NS-398 added in vitro. Patients were randomized to adding the selective COX-2 inhibitor, etoricoxib, or continuing aspirin for 7 days. Etoricoxib significantly reduced by approximately 25% TXM excretion and serum TXB(2). Fourteen of the 41 patients were studied again 21 (+/- 7) months after the first visit. Serum TXB(2) was consistently reduced by approximately 30% by adding NS398 in vitro, while it was completely suppressed with 50 microM aspirin. Accelerated platelet regeneration in most aspirin-treated ET patients may explain aspirin-persistent TXA(2) biosynthesis through enhanced COX-2 activity and faster renewal of unacetylated COX-1. These findings may help in reassessing the optimal antiplatelet strategy in ET.
Assuntos
Aspirina/uso terapêutico , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Piridinas/uso terapêutico , Sulfonas/uso terapêutico , Trombocitemia Essencial/tratamento farmacológico , Tromboxanos/biossíntese , Adulto , Inibidores de Ciclo-Oxigenase/uso terapêutico , Quimioterapia Combinada , Etoricoxib , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Trombocitemia Essencial/metabolismo , Trombocitemia Essencial/patologia , Tromboxano A2/biossíntese , Tromboxano A2/sangue , Tromboxano A2/urina , Tromboxano B2/análogos & derivados , Tromboxano B2/biossíntese , Tromboxano B2/sangue , Tromboxano B2/urina , Tromboxanos/sangue , Tromboxanos/urina , Resultado do TratamentoRESUMO
AIM: Up-regulation of soluble CD40 ligand (sCD40L) and of monocyte chemoattractant protein-1 (MCP-1) has been found in diabetes and in patients with acute cerebral ischemia. We asked whether (i) the two molecules are similarly upregulated among non-lacunar and lacunar diabetic strokes and (ii) sCD40L and/or MCP-1 predict the risk of cardiovascular events in this setting. METHODS: Ninety patients with type 2 diabetes mellitus presenting with an acute ischemic stroke (compared with 45 control subjects) were evaluated on admission and up to 36 months (median 24 months) after the event. RESULTS: Diabetic patients with acute stroke had higher plasma CD40L and MCP-1 than controls (p<0.0001), with no significant differences among lacunar and non-lacunar strokes. On multiple regression analysis, only higher sCD40L quartiles and older age were associated with higher MCP-1 quartiles. Forty-eight percent of patients experienced vascular events. Cox regression analysis showed that only the presence of higher sCD40L values independently predicted the recurrence of vascular events. CONCLUSION: Up-regulation of inflammatory molecules, such as CD40L and MCP-1, is involved in the advanced stage of atherosclerotic cerebro-vascular disease and is associated with increased risk of recurrence of cardiovascular events.
Assuntos
Ligante de CD40/biossíntese , Quimiocina CCL2/biossíntese , Complicações do Diabetes/sangue , Diabetes Mellitus/sangue , Regulação da Expressão Gênica , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/complicações , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Risco , Resultado do TratamentoRESUMO
OBJECTIVE: This study was conducted to assess the thromboxane (TX) dependence of biochemical and functional indexes used to monitor the effect of low-dose aspirin. BACKGROUND: Functional assays of the antiplatelet effects of low-dose aspirin variably reflect the TX-dependent component of platelet aggregation. Previous studies of aspirin resistance were typically based on a single determination of platelet aggregation. METHODS: We assessed the TXB(2) dependence of biochemical and functional indexes, as well as their intersubject and intrasubject variability during administration of the drug and after its withdrawal in 48 healthy volunteers randomized to receive aspirin 100 mg daily for 1 to 8 weeks. RESULTS: Serum TXB(2) was uniformly suppressed by 99% of baseline. Urinary 11-dehydro-TXB(2), arachidonic acid-induced aggregation, and VerifyNow Aspirin (Accumetrics Inc., San Diego, California) showed stable, incomplete inhibition (65%, 80%, and 35%, respectively). Adenosine diphosphate- and collagen-induced aggregation was highly variable and poorly affected by aspirin, with an apparent time-dependent reversal. Inhibition of platelet cyclooxygenase activity was nonlinearly related to inhibition of platelet aggregation. Platelet function largely recovered by day 3 post-aspirin, independently of treatment duration. With any functional assay, occasionally "resistant" subjects were found to be "responders" on previous or subsequent determinations. CONCLUSIONS: Platelet cyclooxygenase activity, as reflected by serum TXB(2) levels, is uniformly and persistently suppressed by low-dose aspirin in healthy subjects. However, the effect of aspirin is variably detected by functional assays, potentially leading to misclassification of "responder" as "resistant" phenotypes owing to poor reproducibility of functional measurements. The nonlinearity of the relationship between inhibition of TX production and inhibition of platelet function has important clinical implications.