Broad-Spectrum Antiviral Activity of Virazole: 1-β-D-Ribofuranosyl-1,2,4-triazole-3-carboxamide

Sidwell, Robert W.; Huffman, John H.; Khare, G. P.; Allen, Lois B.; Witkowski, J. T.; Robins, Roland K.

doi:10.1126/science.177.4050.705

Cited by 970 publications

(531 citation statements)

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“…RBV demonstrated a moderate antiadenoviral effect, confirming previous reports. 42 The high calculated IC 90 of B250 mM might explain the fact that reported clearance of adenovirus infection occurred most frequently in patients with adenovirus-associated hemorrhagic cystitis due to high bladder concentrations of RBV. 43,44,53,74,75 Intravenous RBV administration is associated with anemia due to intravascular hemolysis and bone marrow-suppressive effects.…”

Section: Discussionmentioning

confidence: 99%

“…29,32,40,41 So far, experience is greatest with parenteral administration of the broad-spectrum antiviral ribonucleoside ribavirin (RBV), 41 which has documented activity against adenovirus in vitro. 42 In some cases therapy was successful, [43][44][45][46][47][48] but many patients died despite RBV treatment. [49][50][51][52][53][54][55][56] Furthermore, cidofovir (CDV), an acyclic nucleoside phosphonate that has activity against virtually all DNA viruses including adenovirus, 57,58 has been evaluated for disseminated adenovirus disease with limited success.…”

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confidence: 99%

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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: 99%

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confidence: 99%

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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“…Ribavirin( 1 -B-D-ribo furanosyl-1,2,4-triazole-3-car boxamide) is a synthetic nucleoside analogue structurally similar to guanosine, xanthosine, and pyrazofurin (12). Ribavirin displays antiviral activity against a wide range of DNA and RNA viruses, including some members of the flaviviridae family, to which HCV has been provisionally assigned (12).…”

mentioning

confidence: 99%

“…Ribavirin displays antiviral activity against a wide range of DNA and RNA viruses, including some members of the flaviviridae family, to which HCV has been provisionally assigned (12). This substance also inhibits the in vitro replication of hepatitis A, B, and D (delta) viruses (13)(14)(15).…”

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confidence: 99%

Ribavirin in the treatment of chronic hepatitis C unresponsive to alfa interferon

Camps

Garcı́a

Riezu-Boj

et al. 1993

Journal of Hepatology

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For the 30-50% of patients with chronic hepatitis C who do not respond to a-interferon therapy there is no alternative treatment. Some previously untreated patients have shown a biochemical response to ribavirin, but the antiviral effects of this substance on a-interferon-resistant cases is largely unknown. Twelve patients with chronic hepatitis C who had not responded to a 6-12 month course of a-interferon were included in this study. Oral ribavirin was administered at a dose of 16 mg/kg per day for 6 or 9 months. Aminotransferase levels had not significantly changed during interferon therapy but decreased significantly during ribavirin treatment (mean alanine aminotransferase at baseline, 102 ± 18 IU/I vs. 55 ± 14 IU/I at 6 months; P = 0.0001). Aminotransferase levels became normal in 6 cases (50'V,,), significantly decreased in 3 patients (25'Vo), and did not significantly change in the remaining 3 cases (25'V,,). All patients with normalized aminotransferase values relapsed after ribavirin was discontinued and aminotransferase activity returned to pretreatment levels. Before therapy serum hepatitis C virus RNA was detected by polymerase chain reaction in 10 cases. None of them had cleared viral RNA when tested following 3, 6 and 9 months of ribavirin therapy. Side-effects were mild and reversible. In conclusion, about half of the patients with chronic hepatitis C who are unresponsive to a-interferon show a clear-cut biochemical response after 6-9 months of ribavirin administration. However, ribavirin does not clear circulating hepatitis C virus RNA and relapses occur after withdrawal. Therefore, since ribavirin alone does not appear to suppress viral replication, despite its biochemical effect, further studies should be made in combination with other antiviral substances.

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“…The adenosine analogue 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide (ribavirin) is one such example. This broad-spectrum anti-viral drug has recently been used for the treatment of patients infected with the hepatitis C virus [1,2]. The delivery of a drug across the cell membrane needs to be well understood in order to clarify the mechanism underlying its effects.…”

Section: Introductionmentioning

confidence: 99%

Kinetic study of anti-viral ribavirin uptake mediated by hCNT3 and hENT1 in Xenopus laevis oocytes

Yamamoto

Sugawara

Kikukawa

et al. 2010

Biophysical Chemistry

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Transport across the cell membrane is crucial in drug delivery. However, the process is complicated because nucleoside derivatives that are commonly used as anti-viral drugs are transported through two different types of specific transporter: concentrative transporters and equilibrative transporters. Cross-disciplinary approaches involving both biological experiments and theoretical considerations are therefore necessary to study the transport of nucleoside analogues such as ribavirin. Here we constructed an experimental model system using the Xenopus laevis oocyte that expressed examples of both types of transporter: human concentrative nucleoside transporter 3 and human equilibrative transporter 1. We also performed a kinetic study. Experimental results showed that the transport of ribavirin could be reduced by inhibiting one of the two types of transporter, which seems to be counterintuitive. We therefore designed a simple mathematical model of the dynamics of ribavirin uptake and analyzed the model behaviors using a numerical simulation. The theoretical results reproduced the experimentally observed phenomena and suggested a possible mechanism for the process. Based on this mechanism, we predicted some potential methods for the effective uptake of ribavirin from a dynamics point of view.

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Broad-Spectrum Antiviral Activity of Virazole: 1-β-D-Ribofuranosyl-1,2,4-triazole-3-carboxamide

Cited by 970 publications

References 5 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

Ribavirin in the treatment of chronic hepatitis C unresponsive to alfa interferon

Kinetic study of anti-viral ribavirin uptake mediated by hCNT3 and hENT1 in Xenopus laevis oocytes

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