RESUMEN
Hepatitis C virus (HCV) entry inhibitors (EIs) act synergistically with drugs targeting other stages of the HCV lifecycle. The origin of this synergy remains unknown. Here, we argue that the synergy may arise from the complementary activities of the drugs across cell subpopulations expressing different levels of HCV entry receptors. We employ mathematical modeling of viral kinetics in vitro, where cells with a distribution of entry receptor expression levels are exposed to HCV with or without drugs. The drugs act independently in each cell, as expected in the absence of underlying interactions. Yet, at the cell population level our model predicts that the drugs exhibit synergy. EIs effectively block infection of cells with low receptor levels. With high receptor levels, where EIs are compromised, other drugs are potent. This novel mechanism of synergy, arising at the cell population level may facilitate interpretation of drug activity and treatment optimization.
RESUMEN
Ribavirin, a broad spectrum antiviral agent, in conjunction with interferon forms the current standard of treatment for hepatitis C virus (HCV) infection in humans. While ribavirin alone fails to induce a significant antiviral response, in combination with interferon, ribavirin dramatically improves the long-term outcome of therapy. The predominant mechanism(s) of ribavirin action against HCV, are yet to be established. In this review, we examine the current status of our understanding of the metabolism, pharmacokinetics and mechanisms of the antiviral activity of ribavirin against HCV, all of which are central to the rational identification of improved treatment protocols.
Asunto(s)
Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Ribavirina/farmacología , Antivirales/metabolismo , Antivirales/farmacocinética , Hepatitis C/tratamiento farmacológico , Humanos , Ribavirina/metabolismo , Ribavirina/farmacocinéticaRESUMEN
We propose a kinetic model for describing crystal nucleation kinetics in hard-sphere colloidal suspensions. The model captures the interplay between the enhanced thermodynamic driving force and the reduced particle diffusivity in determining crystal nucleation rates as the particle density is increased in hard-sphere suspensions. Model calculations of nucleation rates and crystal growth velocities agree quantitatively with experimental observations. The dependence of the critical cluster size on volume fraction that emerges differs qualitatively from predictions of classical theories allowing for an experimental validation of the mechanism of crystal nucleation in colloidal suspensions.