Biochemistry and clinical applications of ribavirin

Gilbert, Brian E.; Knight, Vernon

doi:10.1128/aac.30.2.201

Cited by 247 publications

(111 citation statements)

References 45 publications

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“…43,44,53,74,75 Intravenous RBV administration is associated with anemia due to intravascular hemolysis and bone marrow-suppressive effects. 76 The antiadenoviral effects of CDV, which is approved for the treatment of CMV retinitis in AIDS patients, have been described previously for several serotypes including Ad5. 60,61,77,78 However, the IC 50 value in our system was about 10 times lower than previously reported.…”

Section: Discussionmentioning

confidence: 88%

Comparison of HSV-1 thymidine kinase-dependent and -independent inhibition of replication-competent adenoviral vectors by a panel of drugs

et al. 2003

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Replication-competent adenoviral vectors hold the promise to be more efficient gene delivery vehicles than their replicationdeficient counterparts, but they are also associated with a higher risk for adverse effects, especially in light of the fact that there is no established effective therapy for serious, disseminated adenovirus infection. To assess whether the therapeutic options to inhibit adenoviral replication can be enhanced by expressing a suicide gene, we examined the antiadenoviral effects of 15 drugs against wild-type adenovirus type 5 (Ad5) and an Ad5-based replication-competent vector expressing herpes simplex virus-1 thymidine kinase (HSV-tk) (Ad.OW34) using a real-time polymerase chain reaction -based assay and flow cytometry. Ad5 and Ad.OW34 were highly susceptible to the fluorinated pyrimidine analogs 5-fluoro-2 0 -deoxyuridine (FUdR), 5-fluorouridine (FUR), and trifluorothymidine (TFT), with a mean 50% inhibitory concentration (IC 50 ) ranging from 0.12 to 0.32 mM. The mean IC 50 of ribavirin and cidofovir (CDV) for Ad5, the most frequently used drugs to treat adenovirus disease, was 6.87 and 3.19 mM, respectively. In contrast to Ad5, the Ad.OW34 vector was susceptible to (E)-5-(2-bromovinyl)-2 0 -deoxyuridine (BVdU, IC 50 0.09 mM), ganciclovir (GCV, IC 50 0.19 mM), and acyclovir (ACV, IC 50 32.04 mM). Additionally, we demonstrated in an animal model that Ad.OW34 vector replication can be inhibited significantly by GCV, CDV, and TFT by 35.2, 7.7, and 3.7-fold, respectively, compared to untreated animals. The observed antiadenoviral effects were primarily not through cell killing, since the in vitro 50% cytotoxic concentrations (CC 50 ) were more than 1000 times higher than the antiadenoviral IC 50 of the drugs examined, even in cells stably expressing HSV-tk. Since for HSV-tk-dependent inhibition of adenoviral vectors, stability of HSV-tk expression is crucial, we examined Ad.OW34 vector stability, by passaging the vector 10 times serially in the presence of 10 mM GCV. The HSV-tk/GCV system neither changed the susceptibility of Ad.OW34 to GCV significantly nor detectable vector rearrangements occurred, suggesting that the system might be suitable as a fail-safe mechanism to stop adenoviral vector replication.

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Section: Discussionmentioning

confidence: 88%

Comparison of HSV-1 thymidine kinase-dependent and -independent inhibition of replication-competent adenoviral vectors by a panel of drugs

et al. 2003

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“…A high mutation frequency and a susceptibility to error catastrophe also appear to be common traits of most RNA viruses (3,8,40). The experiments reported here used ribavirin concentrations in the range of 100-1,000 M, comparable to concentrations observed in clinical settings (15,36,43). The effectiveness of ribavirin in vivo as an RNA virus mutagen may depend on the accumulation of ribavirin and ribavirin triphosphate in some tissues (such as liver, or respiratory tract epithelium when administered as an aerosol) but not others.…”

Section: Discussionmentioning

confidence: 99%

“…Ribavirin is an antiviral drug that is currently in widespread clinical use to treat hepatitis C, respiratory syncytial virus, and lassa fever virus infections (18)(19)(20)(21). The mechanism of action of ribavirin has been unclear since its discovery almost 30 years ago (20,(35)(36)(37)(38)(39). We previously proposed that ribavirin's antiviral activity is exerted through its potent RNA virus mutagenesis, as a nucleoside analog that becomes incorporated into newly synthesized genomes by the viral RNA-dependent RNA polymerase (15).…”

Section: Discussionmentioning

confidence: 99%

RNA virus error catastrophe: Direct molecular test by using ribavirin

Crotty

Cameron

Andino

2001

Proc. Natl. Acad. Sci. U.S.A.

789

713

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RNA viruses evolve rapidly. One source of this ability to rapidly change is the apparently high mutation frequency in RNA virus populations. A high mutation frequency is a central tenet of the quasispecies theory. A corollary of the quasispecies theory postulates that, given their high mutation frequency, animal RNA viruses may be susceptible to error catastrophe, where they undergo a sharp drop in viability after a modest increase in mutation frequency. We recently showed that the important broad-spectrum antiviral drug ribavirin (currently used to treat hepatitis C virus infections, among others) is an RNA virus mutagen, and we proposed that ribavirin's antiviral effect is by forcing RNA viruses into error catastrophe. However, a direct demonstration of error catastrophe has not been made for ribavirin or any RNA virus mutagen. Here we describe a direct demonstration of error catastrophe by using ribavirin as the mutagen and poliovirus as a model RNA virus. We demonstrate that ribavirin's antiviral activity is exerted directly through lethal mutagenesis of the viral genetic material. A 99.3% loss in viral genome infectivity is observed after a single round of virus infection in ribavirin concentrations sufficient to cause a 9.7-fold increase in mutagenesis. Compiling data on both the mutation levels and the specific infectivities of poliovirus genomes produced in the presence of ribavirin, we have constructed a graph of error catastrophe showing that normal poliovirus indeed exists at the edge of viability. These data suggest that RNA virus mutagens may represent a promising new class of antiviral drugs.

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“…Mice were placed in sealed plastic cages and exposed to aerosols as previously described (5,17). The Collison aerosol generator was the same as previously described (9,17) except that the shape of the reservoir was modified to allow collection of liposomes at the bottom.…”

mentioning

confidence: 99%

“…This change yields a more uniform aerosol. The estimated dose of drug retained by each mouse was calculated from the amount of drug in the aerosol, the minute volume, a retention factor of 0.3, and the duration of treatment, as previously described (5,17).…”

mentioning

confidence: 99%

Aerosolized liposomal amphotericin B for treatment of pulmonary and systemic Cryptococcus neoformans infections in mice

Gilbert

Wyde

Wilson

1992

Antimicrob Agents Chemother

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Cryptococcus infections of the lung and central nervous system have become major problems in immuno-compromised patients, leading to the need for additional treatment protocols. We have utilized a Cryptococcus-mouse model that mimics human cryptococcal disease to evaluate the efficacy of amphotericin B-liposomes (AmpB-Lip) when delivered by small-particle aerosol (SPA). In the model, initial intranasal inoculation leads to a pulmonary infection that spreads after 2 to 3 weeks to distant organs, including the brain. Aerosols of AmpB-Lip that were generated by a Collison nebulizer had mass median aerodynamic diameters of 1.8 microns and contained 10.3 micrograms of AmpB per liter. When AmpB-Lip SPA was begun at 24 h postinoculation, a single 2-h treatment (0.3 mg of AmpB per kg of body weight) was effective in reducing pulmonary Cryptococcus infection. This regimen was more effective than intravenous administration of AmpB-Lip given for 3 continuous days. This single 2-h exposure to AmpB-Lip also was effective in reducing pulmonary Cryptococcus infection when treatment was delayed for 7 or 14 days. At day 21, when organisms had spread to the brain in all animals, the single 2-h aerosol treatment reduced the number of cryptococci in the brain as well as in the lungs. AmpB-Lip SPA administered once for 2 h on days 7, 14, and 21 also was effective in increasing the duration of survival of infected animals. These results demonstrate that aerosolized AmpB-Lip can be effective in treating both local, pulmonary Cryptococcus disease and systemic disease.

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Biochemistry and clinical applications of ribavirin

Cited by 247 publications

References 45 publications

Comparison of HSV-1 thymidine kinase-dependent and -independent inhibition of replication-competent adenoviral vectors by a panel of drugs

Comparison of HSV-1 thymidine kinase-dependent and -independent inhibition of replication-competent adenoviral vectors by a panel of drugs

RNA virus error catastrophe: Direct molecular test by using ribavirin

Aerosolized liposomal amphotericin B for treatment of pulmonary and systemic Cryptococcus neoformans infections in mice

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