RESUMEN
BACKGROUND: Drugs that block platelet-platelet and platelet-fibrin interactions via the alpha(IIb)beta(3) (glycoprotein IIb/IIIa) receptor are used daily in patients undergoing percutaneous coronary interventions. Along with expected increases in spontaneous bleeding, clinical trials have revealed a surprising increase in thrombosis when these drugs are used without other anticoagulants. A better understanding of their mechanisms can minimize these risks. OBJECTIVES: This study tested the hypothesis that interventions designed to block fibrinogen binding inevitably leave the alpha(IIb)beta(3) receptor in an activated state. It compared the effects on platelet function and alpha(IIb)beta(3) conformation of the orally active compounds orbofiban and roxifiban, the i.v. agents eptifibatide and tirofiban, and echistatin, an arginine-glycine-aspartate (RGD) disintegrin. METHODS: The integrin antagonist concentrations required to saturate platelets and to block platelet-platelet and platelet-fibrin interactions were determined by flow cytometry, aggregometry, and clot-based adhesion assays, respectively. Analytical ultracentrifugation measured each antagonist's effects on the solution structure of alpha(IIb)beta(3). Fluorescence anisotropy provided equilibrium and kinetic data for integrin:antagonist interactions. RESULTS: Both orally active drugs bound more tightly and inhibited platelet aggregation and adhesion to fibrin more effectively than echistatin. Analytical ultracentrifugation yielded this order for perturbing alpha(IIb)beta(3) conformation (priming) and promoting oligomerization (clustering): echistatin > eptifibatide > orbofiban > tirofiban > roxifiban. Roxifiban was also most effective at disrupting the rapidly forming/slowly dissociating alpha(IIb)beta(3):echistatin complex. CONCLUSIONS: Our results suggest that the same molecular mechanisms that enable glycoprotein IIb/IIIa inhibitors to bind tightly to the alpha(IIb)beta(3) receptor and block fibrinogen binding contribute to their ability to perturb the resting integrin's conformation, thus limiting the safety and efficacy of both oral and i.v. integrin antagonists.
Asunto(s)
Plaquetas/efectos de los fármacos , Activación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/efectos de los fármacos , Administración Oral , Alanina/farmacología , Amidinas/farmacología , Unión Competitiva , Plaquetas/metabolismo , Dimerización , Relación Dosis-Respuesta a Droga , Eptifibatida , Femenino , Fibrinógeno/metabolismo , Humanos , Técnicas In Vitro , Inyecciones Intravenosas , Péptidos y Proteínas de Señalización Intercelular , Isoxazoles/farmacología , Cinética , Masculino , Modelos Moleculares , Péptidos/farmacología , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/metabolismo , Pruebas de Función Plaquetaria , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/química , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Unión Proteica , Conformación Proteica/efectos de los fármacos , Pirrolidinas/farmacología , Valores de Referencia , Relación Estructura-Actividad , Tirofibán , Tirosina/análogos & derivados , Tirosina/farmacologíaRESUMEN
Over the past few decades, a growing number of studies have been conducted on the mechanisms responsible for climate change and the elaboration of future climate scenarios. More recently, studies have emerged examining the potential effects of climate change on human societies, including how variations in hydrological regimes impact water resources management. According to the Intergovernmental Panel on Climate Change's third assessment report, climate change will lead to an intensification of the hydrological cycle, resulting in greater variability in precipitation patterns and an increase in the intensity and frequency of severe storms and other extreme events. In other words, climate change will likely increase the risks of flooding in many areas. Structural and non-structural countermeasures are available to reduce flood vulnerability, but implementing new measures can be a lengthy process requiring political and financial support. In order to help guide such policy decisions, a method for assessing flood vulnerability due to climate change is proposed. In this preliminary study, multivariate analysis has been used to develop a Flood Vulnerability Index (FVI), which allows for a comparative analysis of flood vulnerability between different basins. Once fully developed, the FVI will also allow users to identify the main factors responsible for a basin's vulnerability, making it a valuable tool to assist in priority setting within decision-making processes.