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1.
Clin Appl Thromb Hemost ; 26: 1076029620959724, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32970454

RESUMO

Use of left ventricular assist devices (LVADs) for management of advanced heart failure is becoming increasingly common; however, device associated thrombosis remains an important cause of mortality in this patient population. We hypothesize that inflammation in LVAD implanted patients dysregulates the protein C pathway, creating a hypercoagulable state leading to thrombosis. Plasma samples from 22 patients implanted with the Thoratec HeartMate II LVAD were analyzed by commercial ELISAs. Retrospective sample selection included those collected 1-3 months prior to and within 1 month after a thrombotic or bleeding event. Unrelated to warfarin dosing, total protein S and free protein S (p = 0.033) levels were 20% lower in patients with LVAD-thrombosis than in patients with LVAD-bleeding. Levels of protein C, soluble endothelial cell protein C receptor, and soluble thrombomodulin were similar in both groups before and after the event. Compared to normal, C-reactive protein levels were 25-fold elevated in LVAD-thrombosis patients but only 9-fold elevated in LVAD-bleeding patients. This study suggests that protein S, influenced by the inflammatory state, is a gatekeeper for the function of protein C in patients with LVAD-associated thrombosis.


Assuntos
Insuficiência Cardíaca/fisiopatologia , Coração Auxiliar/normas , Inflamação/fisiopatologia , Proteína C/fisiologia , Trombose/fisiopatologia , Feminino , Humanos , Masculino
2.
Biomark Med ; 10(10): 1095-1104, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27643569

RESUMO

For heart failure patients unable to undergo cardiac transplantation, mechanical circulatory support with left ventricular assist devices can be utilized. These devices improve quality of life and prolong life expectancy, but they are associated with bleeding and thrombotic complications impacting patient survival. Little is known of the relevant mechanisms of these hemostatic issues, hindering identification of a clinically useful biomarker. However, there is suggestive evidence that blood cell-derived microparticles may fulfill this unmet clinical need. Recent publications have shown an association of up regulated microparticle production with implanted left ventricular assist devices and the potential to use this as a biomarker to predict thrombosis (and perhaps other adverse events) with an onset time earlier than currently used clinical indicators.


Assuntos
Biomarcadores/metabolismo , Micropartículas Derivadas de Células/metabolismo , Insuficiência Cardíaca/diagnóstico , Células Sanguíneas/citologia , Células Sanguíneas/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/terapia , Transplante de Coração , Coração Auxiliar/efeitos adversos , Hemólise , Humanos
3.
Clin Appl Thromb Hemost ; 20(7): 678-86, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25115761

RESUMO

This study was undertaken to provide evidence for the mechanism of venous thromboembolism (VTE) in healthy patients with minor lower limb injury (fracture; Achilles tendon rupture) that was medically managed with plaster cast/brace immobilization. The Plaster Cast clinical trial provided a unique opportunity to identify the natural history of VTE using placebo-controlled patients (n = 183) with validation of the mechanism using the low-molecular-weight heparin (LMWH; reviparin)-treated patients (n = 182). Confirmed VTE in this population was associated with a burst of tissue factor release (and a minor fibrinolytic deficit) leading to thrombin generation that was sustained at least 5 weeks, greater with fractures than with soft-tissue injuries and greater with surgery than with conservative treatment. The root cause likely involves platelet/leukocyte activation (inflammation) rather than endothelial cell injury. Thromboprophylaxis with a low dose of LMWH reduced thrombin generation, with patients undergoing surgery benefitting the most.


Assuntos
Fraturas Ósseas/sangue , Extremidade Inferior/lesões , Traumatismos dos Tendões/sangue , Tromboplastina/metabolismo , Tromboembolia Venosa/sangue , Tromboembolia Venosa/prevenção & controle , Tendão do Calcâneo/lesões , Tendão do Calcâneo/cirurgia , Anticoagulantes/administração & dosagem , Método Duplo-Cego , Feminino , Fraturas Ósseas/cirurgia , Heparina de Baixo Peso Molecular/administração & dosagem , Humanos , Extremidade Inferior/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Traumatismos dos Tendões/cirurgia , Fatores de Tempo , Tromboembolia Venosa/etiologia
4.
Clin Appl Thromb Hemost ; 20(6): 621-8, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23482722

RESUMO

INTRODUCTION: AVE5026 represents a new generation of ultra-low-molecular-weight heparin (LMWH) with high anti-Xa and low anti-IIa activities (anti Xa-IIa ratio >30). In addition, AVE5026 exhibits a relatively higher proportion of AT components. MATERIALS AND METHODS: The anticoagulant, antiplatelet, antithrombotic, and bleeding effects of AVE5026 in comparison to other heparins were investigated in this study. RESULTS: AVE5026 demonstrated weak effects in the global clotting assays; however, in the amidolytic anti-Xa assay, AVE5026 produced strong inhibitory effects. AVE5026 showed no cross-reactivity with the heparin-induced thrombocytopenia antibodies in the platelet aggregation system. AVE5026 produced a dose-dependent antithrombotic response after intravenous (IV) and subcutaneous (SC) administration in thrombosis models. The relative bleeding effects of AVE5026 in a rat tail bleeding and rabbit blood loss model were negligible after both IV and SC administration. CONCLUSIONS: This superior safety efficacy index in animal models in comparison with other LMWH may translate into improved antithrombotic efficacy with decreased bleeding risk.


Assuntos
Inibidores do Fator Xa/farmacologia , Heparina/análogos & derivados , Trombose/tratamento farmacológico , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Heparina/farmacologia , Masculino , Coelhos , Ratos , Ratos Wistar , Trombose/sangue
5.
Clin Appl Thromb Hemost ; 19(5): 482-7, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23780399

RESUMO

Due to the pronounced hypercoagulable state in heparin-induced thrombocytopenia (HIT), alternatives to heparin that do not interact with HIT antibodies are needed for anticoagulation management. This study was designed to determine whether the oral factor Xa inhibitor apixaban could be used. Functional platelet activation with apixaban in the presence of HIT antibodies was evaluated by the (14)C-serotonin release assay (SRA; washed platelets) and the heparin-induced platelet aggregation assay (PA-HIT; platelet-rich plasma). A consistent absence of platelet activation by apixaban (0.05-50 µg/mL) was observed: SRA (n = 35) 11 ± 4% and PA-HIT (n = 37) 8 ± 3% (mean ± standard error of the mean; positive is >20%) versus heparin (0.1 U/mL) 82 ± 3% SRA and 78 ± 6% PA-HIT (P < 0.01) versus enoxaparin (10 µg/mL) 73 ± 5% SRA and 62 ± 7% PA-HIT. Apixaban may provide an option for oral anticoagulation in patients with HIT, particularly for extended management and prevention.


Assuntos
Anticoagulantes/administração & dosagem , Heparina/efeitos adversos , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Trombocitopenia/induzido quimicamente , Trombocitopenia/tratamento farmacológico , Anticoagulantes/efeitos adversos , Plaquetas/efeitos dos fármacos , Plaquetas/imunologia , Feminino , Humanos , Masculino , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Serotonina/sangue , Trombocitopenia/sangue , Trombocitopenia/imunologia
6.
Am J Cardiovasc Dis ; 3(2): 60-70, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23785583

RESUMO

Earlier studies have shown that cardiac myosin binding protein-C (cMyBP-C) is easily releasable into the circulation following myocardial infarction (MI) in animal models and patients. However, since its release kinetics has not been clearly demonstrated, no parameters are available to judge its efficacy as a bona fide biomarker of MI in patients with MI. To make this assessment, plasma levels of cMyBP-C and six known biomarkers of MI were determined by sandwich enzyme-linked immunosorbent assay in patients with MI who had before and after Percutaneous Transcoronary Angioplasty (PTCA), as well as healthy controls. Compared to healthy controls (22.3 ± 2.4 ng/mL (n=54)), plasma levels of cMyBP-C were significantly increased in patients with MI (105.1 ± 8.8 ng/mL (n=65), P<0.001). Out of 65 patients, 24 had very high levels of plasma cMyBP-C (116.5 ± 13.3 ng/mL), indicating high probability of MI. Importantly, cMyBP-C levels were significantly decreased in patients (n=40) at 12 hours post-PTCA (41.2 ± 9.3 ng/mL, P<0.001), compared to the patients with MI. Receiver operating characteristic analysis revealed that a plasma cMyBP-C reading of 68.1 ng/mL provided a sensitivity of 66.2% and a specificity of 100%. Also, myoglobin, carbonic anhydrase and creatine kinase-MB levels were significantly increased in MI patients who also had higher cMyBP-C levels. In contrast, levels of cardiac troponin I, glycogen phosphorylase and heart-type fatty acid binding protein were not significantly changed in the samples, indicating the importance of evaluating the differences in release kinetics of these biomarkers in the context of accurate diagnosis. Our findings suggest that circulating cMyBP-C is a sensitive and cardiac-specific biomarker with potential utility for the accurate diagnosis of MI.

7.
Clin Appl Thromb Hemost ; 19(3): 261-7, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23091283

RESUMO

Enoxaparin, a complex, biologically derived low-molecular-weight heparin, is approved for a range of clinical indications. This study was carried out to compare the potency profile and pharmacodynamic responses of branded enoxaparin (Lovenox; Sanofi, US) with a generic enoxaparin (enoxaparin sodium injection, USP). Five batches of each product were tested. Although the average molecular weight, anti-factor Xa, and anti-factor IIa potencies were similar for the two products, differences were observed in the in vitro thrombin generation and kinetics of clot formation (P = .01) and in the ex vivo pharmacodynamics regarding thrombin generation inhibition (P = .029), tissue factor pathway inhibitor release (P = .006), and inhibition of the active form of thrombin-activated fibrinolysis inhibitor (P = .023). These findings suggest that simple analytical characterization can establish good quality control in manufacturing, but they may not assure similarity in biological performance between the branded and the generic enoxaparin.


Assuntos
Anticoagulantes/farmacologia , Medicamentos Genéricos/farmacologia , Enoxaparina/farmacologia , Área Sob a Curva , Humanos
8.
Clin Appl Thromb Hemost ; 19(3): 249-55, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23162019

RESUMO

Left ventricular assist devices (LVADs) are mechanical pumps that enhance cardiac function in patients with heart failure. In all, 7 patients with an LVADs (1.8 international normalized ratio warfarin, 81 mg aspirin) were evaluated monthly for 3 months for platelet and coagulation activation (controls: 5 healthy adults and 5 patients having warfarin). Platelet works revealed greater inhibition of collagen (31.8% vs 7.9%; P = .004), arachidonate- (30.9% vs 8.2%; P = .001), and adenosine diphosphate- (10.9% vs 6.1%; P = .004)-induced platelet aggregation for LVADs. Thrombelastography (recalcified whole blood) showed inhibition of clot initiation time (R; 8.81 vs 6.02 min; P = .001) and stronger clot formation (maximum amplitude; 69.1 vs 64.9 mm; P = .016). Platelet function determined by plateletMapping and flow cytometry was within the normal range. The LVADs had increased ratio of von Willebrand Factor (vWF) antigen and vWF propeptide, indicating increased degradation of vWF (2.04 vs 1.44; P = .144). Coagulation and platelet activation caused by LVAD is suppressed by pharmacotherapy, yielding a profile similar to that of patients on warfarin alone.


Assuntos
Anticoagulantes/uso terapêutico , Coagulação Sanguínea , Coração Auxiliar , Ativação Plaquetária , Adulto , Idoso , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tromboelastografia
9.
J Thromb Thrombolysis ; 33(3): 230-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22234748

RESUMO

Low-molecular-weight heparins (LMWHs) have shown equivalent or superior efficacy and safety to unfractionated heparin as antithrombotic therapy for patients with acute coronary syndromes. Each approved LMWH is a pleotropic biological agent with a unique chemical, biochemical, biophysical and biological profile and displays different pharmacodynamic and pharmacokinetic profiles. As a result, LMWHs are neither equipotent in preclinical assays nor equivalent in terms of their clinical efficacy and safety. Previously, the US Food and Drug Administration (FDA) cautioned against using various LMWHs interchangeably, however recently, the FDA approved generic versions of LMWH that have not been tested in large clinical trials. This paper highlights the bio-chemical and pharmacological differences between the LMWH preparations that may result in different clinical outcomes, and also reviews the implications and challenges physicians face when generic versions of the original/innovator agents are approved for clinical use.


Assuntos
Produtos Biológicos/uso terapêutico , Aprovação de Drogas/métodos , Medicamentos Genéricos/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Papel do Médico , Animais , Produtos Biológicos/efeitos adversos , Produtos Biológicos/normas , Medicamentos Genéricos/efeitos adversos , Medicamentos Genéricos/normas , Heparina de Baixo Peso Molecular/efeitos adversos , Heparina de Baixo Peso Molecular/normas , Humanos , Guias de Prática Clínica como Assunto/normas , Estados Unidos
10.
Thromb Res ; 128(4): 361-7, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21458847

RESUMO

INTRODUCTION: Lower low-molecular-weight heparins are being developed to improve on the safety and efficacy of antithrombotic therapy. Semuloparin and bemiparin are two depolymerized heparins produced by distinct manufacturing processes. The objective of this investigation was to determine whether a common standard could be used to define their potency. MATERIALS AND METHODS: Activities were compared using typical clinical coagulation assays and pharmacological assays required for potency assessment. RESULTS: The activity of semuloparin and bemiparin was comparable in FXa-based assays (anti-FXa, Heptest). However, bemiparin produced a stronger effect in the aPTT, ACT and anti-thrombin assays. Assessment of the parallelism of the concentration-response curves indicated that bemiparin and semuloparin are not equivalent in terms of anti-FIIa activity. Bemiparin had a stronger inhibitory effect on thrombin induced platelet aggregation, and a stronger interaction with HIT antibodies. CONCLUSIONS: These data demonstrate that depolymerized heparins can exhibit a range of biologic activities making them unique agents. Pharmacopoeial parameters such as anti-IIa and anti-Xa potency and molecular weight are insufficient to characterize such agents.


Assuntos
Testes de Coagulação Sanguínea/normas , Coagulação Sanguínea/efeitos dos fármacos , Fibrinolíticos/farmacologia , Heparina de Baixo Peso Molecular/farmacologia , Testes de Função Plaquetária/normas , Autoanticorpos/metabolismo , Relação Dose-Resposta a Droga , Inibidores do Fator Xa , Fibrinolíticos/química , Fibrinolíticos/imunologia , Heparina de Baixo Peso Molecular/química , Heparina de Baixo Peso Molecular/imunologia , Humanos , Estrutura Molecular , Peso Molecular , Tempo de Tromboplastina Parcial/normas , Agregação Plaquetária/efeitos dos fármacos , Fator Plaquetário 4/imunologia , Protrombina/antagonistas & inibidores , Padrões de Referência , Relação Estrutura-Atividade , Trombina/metabolismo , Tempo de Coagulação do Sangue Total/normas
11.
Blood Coagul Fibrinolysis ; 22(3): 206-10, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21297455

RESUMO

Fondaparinux (Arixtra) is an antithrombin (AT)-dependent synthetic inhibitor of factor Xa (FXa). We undertook a study to determine the ramifications of varying levels of circulating AT on the pharmacologic activity of fondaparinux. AT-deficient human plasma supplemented with 0.125-2.0 U/ml purified human AT and plasmas from liver disease patients (n = 20; 0.3 U/ml AT) were supplemented with fondaparinux (0.125-12.5 µg/ml) then assayed by an amidolytic anti-FXa assay and the clot-based Heptest. A decrease in fondaparinux activity was observed with AT levels of 0.5 U/ml that became more pronounced with decreasing AT levels. For 0.2-1.5 µg/ml fondaparinux (plasma concentrations achieved with dosages for prophylaxis and treatment of venous thromboembolism) and AT levels of 0.5 U/ml there was 20% loss of activity and with 0.25 U/ml AT there was a 45% loss of activity compared to 1 U/ml AT. Increasing AT levels to over 0.5 U/ml or increasing fondaparinux concentrations for AT levels between 0.5 and 1 U/ml achieved fondaparinux activity comparable to that obtained with 1 U/ml AT. With AT levels above 1.0 U/ml a greater inhibitory activity was achieved. The observed potency of fondaparinux in terms of anti-FXa activity was reduced approximately three-fold in patients with liver disease. These in-vitro findings were confirmed in a rabbit model of stasis thrombosis. With AT levels below 30% of normal induced by anti-AT antibodies, there was a 60% in-vivo reduction in the antithrombotic activity of fondaparinux (ED50 75 vs. 240 µg/kg). In summary, the AT level is a rate-limiting factor for the antithrombotic activity of fondaparinux.


Assuntos
Anticoagulantes/farmacologia , Proteínas Antitrombina/metabolismo , Inibidores do Fator Xa , Polissacarídeos/farmacologia , Trombose/tratamento farmacológico , Animais , Anticoagulantes/uso terapêutico , Fondaparinux , Humanos , Hepatopatias/sangue , Polissacarídeos/uso terapêutico , Coelhos
12.
Clin Appl Thromb Hemost ; 17(2): 197-201, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21159704

RESUMO

This study was performed to develop a simple scoring system to aid in the early clinical management of patients suspected of heparin-induced thrombocytopenia (HIT) with regard to decisions for continued heparin therapy. The system was designed to arrive at low (0) or possible (1) probability scores without knowledge of laboratory test results (except platelet counts) to avoid delays. As the safest clinical approach is to discontinue heparin, intermediate and high scores were combined. Critically ill VA hospital patients (n = 100) with a ≥30% fall in platelet count were assessed by platelet aggregation (PA), (14)C-serotonin release assay ((14)C-SRA), and GTI ELISA. In this population, 53% were scored 1 and of these 43% were positive by laboratory test. Emphasizing the decision to discontinue heparin, the clinical signs of HIT were paramount for the immediate determination of a diagnosis of HIT without dependence on a positive laboratory test.


Assuntos
Anticoagulantes/efeitos adversos , Heparina/efeitos adversos , Monitorização Fisiológica/métodos , Trombocitopenia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Ensaio de Imunoadsorção Enzimática , Feminino , Heparina/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária , Contagem de Plaquetas , Serotonina/sangue , Trombocitopenia/sangue , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnóstico , Fatores de Tempo
13.
Expert Rev Hematol ; 3(5): 527-39, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21083469

RESUMO

Argatroban is a synthetic, small-molecule direct thrombin inhibitor that is approved in the USA, the EU and Japan for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT), and for anticoagulation of HIT patients undergoing PCI. Argatroban binds reversibly to, and inhibits both soluble and clot-bound thrombin. Argatroban does not generate antibodies, is not susceptible to degradation by proteases and is cleared hepatically. It has a predictable anticoagulant effect and there is a good correlation between dose, plasma concentration and pharmacodynamic effect. Initial clinical studies suggest that further investigations to establish the use of argatroban in ischemic stroke, acute coronary syndrome, hemodialysis, blood oxygenation, off-pump cardiac surgery and other clinical indications are warranted.


Assuntos
Antitrombinas/farmacologia , Peptidomiméticos/farmacologia , Ácidos Pipecólicos/farmacologia , Trombina/antagonistas & inibidores , Trombose/tratamento farmacológico , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/prevenção & controle , Antitrombinas/química , Antitrombinas/uso terapêutico , Arginina/análogos & derivados , União Europeia , Feminino , Heparina/efeitos adversos , Humanos , Isomerismo , Japão , Masculino , Peptidomiméticos/química , Peptidomiméticos/uso terapêutico , Ácidos Pipecólicos/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle , Sulfonamidas , Trombina/metabolismo , Trombocitopenia/induzido quimicamente , Trombocitopenia/tratamento farmacológico , Trombocitopenia/prevenção & controle , Trombose/prevenção & controle , Estados Unidos
14.
Methods Mol Biol ; 663: 133-56, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20617416

RESUMO

The clinical effects of heparin are meritorious and heparin remains the anticoagulant of choice for most clinical needs. However, as with any drug, adverse effects exist. Heparin-induced thrombocytopenia (HIT) is an important adverse effect of heparin associated with amputation and death due to thrombosis. Although the diagnosis and treatment of HIT can be difficult and complex, it is critical that patients with HIT be identified as soon as possible to initiate early treatment to avoid thrombosis.


Assuntos
Técnicas de Laboratório Clínico/métodos , Heparina/efeitos adversos , Trombocitopenia/diagnóstico , Trombocitopenia/terapia , Animais , Inibidores do Fator Xa , Humanos , Trombina/antagonistas & inibidores , Trombocitopenia/induzido quimicamente , Trombocitopenia/complicações
15.
Methods Mol Biol ; 663: 221-8, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20617420

RESUMO

Novel adenosine diphosphate (ADP) P2Y(12) antagonists such as prasugrel, ticagrelor, cangrelor, and elinogrel are in various phases of clinical development. These ADP P2Y(12) antagonists have advantages over clopidogrel ranging from faster onset to greater and less variable inhibition of platelet function. Novel ADP P2Y(12) antagonists are under investigation to determine whether their use can result in improved antiplatelet activity, faster onset of action, and/or greater antithrombotic effects than clopidogrel without an unacceptable increase in hemorrhagic or other side effects. Prasugrel (CS-747; LY-640315), a novel third-generation oral thienopyridine, is a specific, irreversible antagonist of the platelet ADP P2Y(12) receptor. Pre-clinical and early phase clinical studies have shown prasugrel to be characterized by more potent antiplatelet effects, lower inter-individual variability in platelet response, and faster onset of activity compared to clopidogrel. Recent findings from large-scale phase-III testing show prasugrel to be more efficacious in preventing ischemic events in acute coronary syndrome patients undergoing percutaneous coronary intervention (PCI); however, this is achieved at the expense of an increased risk of bleeding. Prasugrel provides more rapid and consistent platelet inhibition than clopidogrel.


Assuntos
Piperazinas/farmacologia , Antagonistas do Receptor Purinérgico P2 , Tiofenos/farmacologia , Ensaios Clínicos como Assunto , Humanos , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/metabolismo , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Cloridrato de Prasugrel , Tiofenos/farmacocinética , Tiofenos/uso terapêutico
16.
Clin Appl Thromb Hemost ; 16(2): 170-6, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20299391

RESUMO

Novel adenosine diphosphate (ADP) P2Y(12) antagonists, including prasugrel, ticagrelor, cangrelor and elinogrel, are in various phases of clinical development. These ADP P2Y(12) antagonists have advantages over clopidogrel ranging from faster onset to greater and less variable inhibition of platelet function. Novel ADP P2Y(12) antagonists are under investigation to determine whether their use can result in improved antiplatelet activity, faster onset of action, and/or greater antithrombotic effects than clopidogrel, without an unacceptable increase in hemorrhagic or other side effects. Prasugrel (CS-747; LY-640315), a novel third-generation oral thienopyridine, is a specific, irreversible antagonist of the platelet ADP P2Y(12) receptor. Preclinical and early phase clinical studies have shown prasugrel to be characterized by more potent antiplatelet effects, lower interindividual variability in platelet response, and faster onset of activity compared to clopidogrel. Recent findings from large-scale phase III testing showed prasugrel to be more efficacious in preventing ischemic events in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI); however, this is achieved at the expense of an increased risk of bleeding. Prasugrel provides more rapid and consistent platelet inhibition than clopidogrel.


Assuntos
Piperazinas/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Antagonistas do Receptor Purinérgico P2 , Tiofenos/farmacologia , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/terapia , Angioplastia Coronária com Balão , Aspirina/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Clopidogrel , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Hemorragia/induzido quimicamente , Humanos , Isquemia/prevenção & controle , Falência Renal Crônica/metabolismo , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/farmacocinética , Inibidores da Agregação Plaquetária/uso terapêutico , Cloridrato de Prasugrel , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores Purinérgicos P2Y12 , Tiofenos/efeitos adversos , Tiofenos/farmacocinética , Tiofenos/uso terapêutico , Ticlopidina/análogos & derivados , Ticlopidina/uso terapêutico
17.
Thromb Res ; 125(4): e143-8, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19931120

RESUMO

BACKGROUND: Many heparin-induced thrombocytopenia (HIT) antibodies cause platelet activation in the serotonin release assay (SRA) in the absence of heparin. This in vitro observation may help unravel the mechanism of delayed-onset HIT, where seropositive patients develop thrombocytopenia and associated thrombosis after cessation of heparin. OBJECTIVE: Studies were conducted to examine the relationship between platelet environment, surface PF4 expression, and the extent of heparin-independent platelet activation in the SRA. METHODS: Ex vivo platelets were washed and labeled for SRA, then used either before or after 45 minutes of recovery at 37 degrees C. HIT antibody-mediated serotonin release in the absence of heparin was compared to the extent of surface staining of the platelets with fluorescent anti-human PF4 antibodies. RESULTS: Handling of platelets for in vitro studies resulted in transient expression of surface PF4, and it was during this interval that platelets were most sensitive to activation by HIT antibodies in the absence of heparin. Heparin-independent platelet activation was attenuated when SRA-positive specimens were retested after platelets were incubated 45 minutes at 37 degrees C. Surface PF4 expression was diminished on the rested platelets, compared to the same platelets labeled immediately after handling. Thus compared to rested platelets, mildly activated platelets had elevated surface PF4 expression and a higher level of HIT antibody-mediated, heparin-independent platelet activation. CONCLUSION: Surface expression of PF4 reflects HIT antigen presentation, and varies with the physiological state of platelets. Thus there can be differences in HIT antibody target availability among patients which may explain the variability in consequences of HIT antibody seropositivity.


Assuntos
Autoanticorpos/farmacologia , Heparina/imunologia , Ativação Plaquetária/efeitos dos fármacos , Fator Plaquetário 4/imunologia , Trombocitopenia/induzido quimicamente , Anticorpos/efeitos adversos , Anticorpos/imunologia , Anticorpos/farmacologia , Anticorpos Anti-Idiotípicos/efeitos adversos , Anticorpos Anti-Idiotípicos/imunologia , Anticorpos Anti-Idiotípicos/farmacologia , Autoanticorpos/efeitos adversos , Autoanticorpos/imunologia , Plaquetas/imunologia , Plaquetas/metabolismo , Estruturas Celulares/imunologia , Estruturas Celulares/metabolismo , Técnicas de Laboratório Clínico/efeitos adversos , Heparina/metabolismo , Heparina/farmacologia , Humanos , Masculino , Ativação Plaquetária/imunologia , Contagem de Plaquetas , Fator Plaquetário 4/metabolismo , Fator Plaquetário 4/farmacologia , Trombocitopenia/etiologia , Trombocitopenia/imunologia , Trombose/complicações , Trombose/imunologia
18.
Clin Appl Thromb Hemost ; 15(2): 137-44, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19357102

RESUMO

Low-molecular-weight heparins (LMWHs) are poly-pharmacologic drugs used to treat thrombotic and cardiovascular disorders. Recently, several generic versions of branded LMWHs have been introduced. Although generic versions of LMWHs exhibit similar profiles, marked differences in their biological and pharmacologic properties have been demonstrated. Several studies have demonstrated differences in terms of anti-Xa activity and tissue factor pathway inhibitor release. The current data emphasize the need to consider multiple functional parameters when defining bioequivalence of biologic drugs and also underscore the importance of further pharmacologic studies involving animal and human clinical trials. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) are currently developing guidelines for the acceptance of complex biological drugs including LMWHs. The US FDA considers these drugs as follow-on agents whereas the EMEA classifies these drugs as biosimilar agents. Until clear guidelines are developed, generic interchange of LMWHs may not be feasible.


Assuntos
Medicamentos Genéricos/química , Heparina de Baixo Peso Molecular/química , Medicamentos Genéricos/farmacocinética , Medicamentos Genéricos/farmacologia , Guias como Assunto , Heparina de Baixo Peso Molecular/farmacocinética , Heparina de Baixo Peso Molecular/farmacologia , Humanos , Equivalência Terapêutica , Estados Unidos , United States Food and Drug Administration
19.
Br J Haematol ; 143(1): 92-9, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18671707

RESUMO

Rivaroxaban is an oral, direct activated Factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. Currently available anticoagulants include unfractionated heparin (UFH) and low molecular weight heparins (LMWHs); however, their use can be restricted by heparin-induced thrombocytopenia (HIT). HIT is usually caused by the production of antibodies to a complex of heparin and platelet factor-4 (PF4). This study was performed to evaluate, in vitro, the potential of rivaroxaban as an anticoagulant for the management of patients with HIT. UFH, the LMWH enoxaparin, fondaparinux and the direct thrombin inhibitor argatroban were tested to enable comparative analyses. Rivaroxaban did not cause platelet activation or aggregation in the presence of HIT antibodies, unlike UFH and enoxaparin, suggesting that rivaroxaban does not cross-react with HIT antibodies. Furthermore, rivaroxaban did not cause the release of PF4 from platelets and did not interact with PF4, unlike UFH and enoxaparin. These findings suggest that rivaroxaban may be a suitable anticoagulant for the management of patients with HIT.


Assuntos
Anticoagulantes/efeitos adversos , Antitrombina III/uso terapêutico , Heparina de Baixo Peso Molecular/efeitos adversos , Morfolinas/uso terapêutico , Tiofenos/uso terapêutico , Trombocitopenia/induzido quimicamente , Trombocitopenia/tratamento farmacológico , Análise de Variância , Anticoagulantes/uso terapêutico , Arginina/análogos & derivados , Autoanticorpos/imunologia , Enoxaparina/efeitos adversos , Citometria de Fluxo , Fondaparinux , Humanos , Ácidos Pipecólicos/efeitos adversos , Ativação Plaquetária , Agregação Plaquetária/efeitos dos fármacos , Fator Plaquetário 4/efeitos adversos , Polissacarídeos/efeitos adversos , Rivaroxabana , Sulfonamidas , Trombocitopenia/imunologia
20.
Semin Thromb Hemost ; 34(1): 74-85, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18393144

RESUMO

Low-molecular-weight heparins (LMWHs) are polypharmacologic drugs used to treat thrombotic and cardiovascular disorders. These drugs are manufactured using different chemical and enzymatic methods, resulting in products with distinct chemical and pharmacologic profiles. Generic LMWHs have been introduced in Asia and South America, and several generic suppliers are seeking regulatory approval in the United States and the European Union. For simple small-molecule drugs, generic drugs have the same chemical structure, potency, and bioavailability as the innovator drug. Applying this definition to complex biological products such as the LMWHs has proved difficult. One major issue is defining appropriate criteria to demonstrate bioequivalence; pharmacopoeial specifications alone appear to be inadequate. Whereas available generic versions of LMWHs exhibit similar molecular and pharmacopoeial profiles, marked differences in their biological and pharmacologic behavior have been noted. Preliminary studies have demonstrated differences in terms of anti-Xa activity and tissue factor pathway inhibitor release after subcutaneous administration, as well as antiplatelet and profibrinolytic effects. The current data emphasize the need to consider multiple functional parameters when defining bioequivalence of biologic drugs with complex structures and activities and also underscore the importance of further pharmacologic studies involving animal models and human clinical trials. The U.S. Food and Drug Administration and the European Medicine Evaluation Agency are currently developing guidelines for the acceptance of biosimilar agents including LMWHs. Until such guidelines are complete, generic interchange may not be feasible.


Assuntos
Heparina de Baixo Peso Molecular/química , Heparina de Baixo Peso Molecular/farmacologia , Disponibilidade Biológica , Aprovação de Drogas , Medicamentos Genéricos/química , Medicamentos Genéricos/farmacocinética , Medicamentos Genéricos/farmacologia , Inibidores do Fator Xa , Heparina de Baixo Peso Molecular/farmacocinética , Humanos , Peso Molecular , Protrombina/antagonistas & inibidores , Equivalência Terapêutica , Estados Unidos , United States Food and Drug Administration
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