The ribavirin analog ICN 17261 demonstrates reduced toxicity and antiviraleffects with retention of both immunomodulatory activity and reduction of hepatitis-induced serum alanine aminotransferase levels
Rc. Tam et al., The ribavirin analog ICN 17261 demonstrates reduced toxicity and antiviraleffects with retention of both immunomodulatory activity and reduction of hepatitis-induced serum alanine aminotransferase levels, ANTIM AG CH, 44(5), 2000, pp. 1276-1283
The demonstrated utility of the nucleoside analog ribavirin in the treatmen
t of certain viral diseases can be ascribed to its multiple distinct proper
ties. These properties may vary in relative importance in differing viral d
isease conditions and include the direct inhibition of viral replication, t
he promotion of T-cell-mediated immune responses via an enhanced type 1 cyt
okine response, and a reduction of circulating alanine aminotransferase (AL
T) levels associated with hepatic injury. Ribavirin also has certain known
toxicities, including the induction of anemia upon chronic administration.
To determine if all these properties are linked, we compared the D-nucleosi
de ribavirin to its L-enantiomer (ICN 17261) with regard to these propertie
s. Strong similarities were seen for these two compounds with respect to in
duction of type 1 cytokine bias in vitro, enhancement of type 1 cytokine re
sponses in vivo, and the reduction of serum ALT levels in a murine hepatiti
s model. In contrast, ICN 17261 had no in vitro antiviral activity against
a panel of RNA and DNA viruses, while ribavirin exhibited its characteristi
c activity profile, Importantly, the preliminary in vivo toxicology profile
of ICN 17261 is significantly more favorable than that of ribavirin. Admin
istration of 180 mg of ICN 17261 per kg of body weight to rats by oral gava
ge for 4 weeks generated substantial serum levels of drug but no observable
clinical pathology, whereas equivalent doses of ribavirin induced a signif
icant anemia and leukopenia. Thus, structural modification of ribavirin can
dissociate its immunomodulatory properties from its antiviral and toxicolo
gic properties, resulting in a compound (ICN 17261) with interesting therap
eutic potential.