Narrow Therapeutic Window of Ribavirin as an Inhibitor
of Nitric Oxide Synthesis is Broadened by Macromolecular Prodrugs
- Publication date
- Publisher
Abstract
Ribavirin (RBV), a broad-spectrum
antiviral agent, is a standard
medication against hepatitis C virus (HCV). However, despite the decades
of clinical success, the mechanism of action of this drug against
HCV remains a subject of debate. Furthermore, the appeal of this therapeutic
agent is considerably lessened by unfavorable pharmacokinetics. This
interdisciplinary study contributes to the understanding of intracellular
effects exerted by RBV and presents a successful design of macromolecular
prodrugs of RBV to achieve a safer treatment. Specifically, we demonstrate
that RBV exhibits a pronounced anti-inflammatory activity in cultured
macrophages as is evidenced by a 2-fold decrease in the levels of
produced nitric oxide achieved using a clinically relevant concentration
of this drug. However, this effect was characterized by a rather narrow
therapeutic window with experimental values of EC<sub>50</sub> and
IC<sub>50</sub> being 7 and 19 μM, respectively. Macromolecular
prodrugs were obtained using an acrylate derivative of RBV, RAFT polymerization
technique, and <i>N</i>-vinyl pyrrolidone as a partner monomer.
The synthesized polymers were characterized with uniform molecular
weights, relatively narrow polydispersities, and gradually increasing
content of RBV. The resulting polymer therapeutics were effective
in delivering their payload to the cultured macrophages and afforded
a significantly wider therapeutic window, as much as >1000 μM
(18-fold in relative values). Taken together, this work contributes
significantly to the development of safer methods for delivery of
RBV, as well as understanding the mechanism of action and origins
of the side effects of this broad-spectrum antiviral agent