RESUMO
Anticoagulant therapy, combined with platelet-directed inhibitors, represents a standard-of-care in the management of patients with acute coronary syndrome, particularly those who require percutaneous coronary interventions. While a vast clinical experience, coupled with large clinical trials have collectively provided guidance, an optimal anticoagulant drug and applied strategy, defined as one that reduces thrombotic and hemorrhagic events consistently, with minimal off-target effects and active control of systemic anticoagulation according to patient and clinical-setting specific need, remains at large. An advancing knowledge of coagulation, hemostasis, and thrombosis suggests that factor IXa, a protease that governs thrombin generation in common thrombotic disorders may represent a prime target for pharmacologic inhibition.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Fator IXa/antagonistas & inibidores , Síndrome Coronariana Aguda/sangue , Animais , Anticorpos Monoclonais/uso terapêutico , Aptâmeros de Nucleotídeos/uso terapêutico , Sítios de Ligação , Plaquetas/fisiologia , Fator IXa/metabolismo , Hemofilia B/sangue , Humanos , Ligação Proteica , Trombose/etiologiaRESUMO
Thrombotic disorders and their common clinical phenotypes of acute myocardial infarction, ischemic stroke, and venous thromboembolism are the proximate cause of substantial morbidity, mortality, and health care expenditures worldwide. Accordingly, therapies designed to attenuate thrombus initiation and propagation, reflecting integrated platelet-mediated and coagulation protease-mediated events, respectively, represent a standard of care. Unfortunately, there are numerous inherent limitations of existing therapies that include target nonselectivity, variable onset and offset of pharmacodynamic effects, a narrow efficacy-safety profile, and the absence of a safe and reliable platform for either accurate titration, based on existing patient-specific, disease-specific, and clinical conditions, or active reversibility. Herein, we summarize our experience with oligonucleotide antithrombotic agents and their complementary antidotes, targeting the platelet adhesive protein von Willebrand factor and the pivotal coagulation protease factor IXa.
Assuntos
Antídotos/uso terapêutico , Aptâmeros de Nucleotídeos/uso terapêutico , Fator IXa/antagonistas & inibidores , Fibrinolíticos/uso terapêutico , Oligorribonucleotídeos/uso terapêutico , Trombose/terapia , Fator de von Willebrand/antagonistas & inibidores , Plaquetas/metabolismo , Humanos , Técnica de Seleção de AptâmerosRESUMO
Currently available anticoagulants are limited by modest therapeutic benefits, narrow clinical applications, increased bleeding risk, and drug-induced thrombophilia. Because factor IX plays a pivotal role in tissue factor (TF)-mediated thrombin generation, it may represent a promising target for drug development. Several methods of attenuating factor IX activity, including monoclonal antibodies, synthetic active site-blocked competitive inhibitors, oral inhibitors, and RNA aptamers, have undergone investigation. This review summarizes present knowledge of factor IX inhibitors with emphasis on biology, pharmacology, preclinical data, and early-phase clinical experience in humans.
Assuntos
Anticoagulantes/farmacologia , Fator IXa/antagonistas & inibidores , Animais , Anticorpos Monoclonais/farmacologia , Aptâmeros de Nucleotídeos/farmacologia , Coagulação Sanguínea/fisiologia , Fator IX/química , Fator IX/fisiologia , Fator IXa/imunologia , Humanos , Relação Estrutura-AtividadeRESUMO
Nucleic acid 'aptamers', a term derived from the Latin word aptus, 'to fit', are RNA or DNA oligonucleotides that conform to the three-dimensional structure of a selected protein, peptide or small molecules' functional moiety. The 'lock and key' relationship between aptamers and their binding partner permits distinction between closely related but non-identical members of a protein family, or between different functional or conformational states of the same protein. This, along with other properties, separates aptamers from antibodies--the most popular class of molecular recognition tool for the past three decades. Despite the chemical, biological and manufacturing advantages offered by nucleic acid aptamers in a wide variety of conditions, and their generation against a range of clinically relevant targets, including growth factors, transcription factors and coagulation proteins, by two dozen or more companies devoted to the technology platform, only one aptamer, developed for the treatment of wet age-related macular degeneration, is currently available for use in humans. Nevertheless, phase I and II clinical trials for several indications are proceeding with considerable enthusiasm. The potential application of nucleic acid aptamers in novel arenas, including molecular imaging, vaccine development, immunomodulation, decoys for natural RNA-binding events, antiviral therapeutics and both cancer prophylaxis and treatment, is emerging with a pioneering mentality destined to change the paradigm of patient care.
Assuntos
Aptâmeros de Nucleotídeos/uso terapêutico , Ácidos Nucleicos/uso terapêutico , Vacinas/imunologia , Animais , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/farmacologia , Humanos , Modelos Biológicos , Ácidos Nucleicos/química , Ácidos Nucleicos/farmacologia , Técnica de Seleção de AptâmerosRESUMO
BACKGROUND: Temperature variation within human atheromatous plaques, a finding which supports inflammatory cell-mediated thermogenesis, predicts clinical events among patients with coronary artery disease. PURPOSE: Our study was designed to investigate the effect of ambient temperature in vitro on platelet-leukocyte interactions, monocyte tissue factor expression and platelet-dependent thrombin generation. METHODS/RESULTS: Whole blood samples obtained from healthy volunteers were incubated at 37 degrees, 38 degrees and 39 degrees C for three hours. Platelet-leukocyte aggregates, determined by flow cytometry before and after stimulation with lipopolysaccharide (10 ng/ml), increased from 15.0 +/- 2.3% at 37 degrees C to 19.4% at 38 degrees C (22.6% increase; p < 0.01), decreasing to 12.2 +/- 0.9% at 39 degrees C. The responses for individual subpopulations of platelet-lymphocyte, platelet-neutrophil and platelet-monocyte heterotypic aggregates were similar. Monocyte tissue factor expression, quantitated by flow cytometry with CD14 and FITC-labeled anti-human tissue factor antibody stains, increased from 45.2 +/- 3.8% (37 degrees C) to 62.0 +/- 4.3 (38 degrees C), representing a 27.1% rise (p < 0.005). Changes in temperature did not influence the initiation or propagation phases of platelet-dependent thrombin generation. CONCLUSION: A modest increase in ambient temperature increases platelet-leukocyte and monocyte tissue factor expression, providing an additional mechanistic link between atherosclerosis, inflammation and thrombosis. Whether therapies designed to lower vessel wall temperature will provide an antithrombotic effect requires further evaluation.