Suppression by 1-β-
            <scp>d</scp>
            -Ribofuranosyl-1,2,4-Triazole-3-Carboxamide (Virazole, ICN 1229) of Influenza Virus-Induced Infections in Mice

Ribavirin (1-,8-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), a new synthetic nucleoside, inhibited murine cytomegalovirus in cell culture. This was shown by the inhibition of viral cytopathic effect and plaque formation, as well as reduction in the yield of virus. Despite this in vitro antiviral effect, ribavirin did not protect mice from mortality produced by a high inoculum of cytomegalovirus. When a lower inoculum was used to initiate a chronic infection, the administration of ribavirin for 9 days had no effect on the titer of cytomegalovirus in the salivary gland, kidney, liver, and spleen. Thus, ribavirmin was ineffective in the treatment of both acute and chronic murine cytomegalovirus infections.Cytomegalovirus causes a broad spectrum of clinical illnesses including congenital infection, the mononucleosis syndrome, and involvement of various organs in immunosuppressed hosts (18). Human cytomegaloviruses (HCMV) are inhibited by the nucleoside analogues adenine arabinoside, cytosine arabinoside, and 5-iodo-2'-deoxyuridine in cell culture (4). In clinical trials, these antiviral agents may transiently suppress urinary excretion of HCMV, but generally fail to eradicate the virus or alter the natural course of disease (2,3,8,9,13). The search for antiviral agents capable of inhibiting HCMV should therefore be continued.Rivavirin (1-,3-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a new synthetic nucleoside which is active in cell culture against numerous deoxyribonucleic acid and ribonucleic acid viruses (5). The in vitro inhibition of herpesviruses, including murine cytomegalovirus (MCMV), by ribavirin has compared favorably with other antiviral compounds (5,14,19). In animal systems, ribavirin demonstrated activity against influenza A and B (7), vaccinia (15), and herpes simplex (15) infections. The infection in mice produced by MCMV is well characterized (10,11,20) and has been used as a model to evaluate the effectiveness of chemotherapeutic agents (6). This work examines the activity of ribavirin against MCMV in cell culture and in mice. The antiviral effect in cultured cells was first determined by three methods. Then, ribavirin was evaluated in both acute, lethal and chronic, subclinical murine infections. Cell culture. MCMV was grown in secondary mouse embryo tissue culture (METC) maintained with medium 199 supplemented with 2% newborn calf serum, 0.2% NaHCO3, penicillin (100 U/ml), streptomycin (100 ,.tg/ml), and nystatin (50 U/ml). Titration was carried out in METC by the plaquing method using tragacanth overlay (12). After 7 days, the tragacanth was removed and the cell sheets were stained with a dye-fixer solution containing 0.5% methylrosaniline chloride, 5% formalin (vol/ vol), 50%o ethanol (vol/vol), and 0.85% NaCl in distilled water (1). Plaques were enumerated with the aid of a dissecting microscope.Ribavirin. Ribavirin was kindly supplied by Robert W. Sidwell (ICN Nucleic Acid Research Institute, Irvine, Calif.). CPE inhibition. MCMV was added to METC in tube cultures. After virus adsorp...

Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of Ribavirin on Murine Cytomegalovirus Infection

Dowling

Postic

Guevarra

1976

“…Recently, ribavirin (1-3-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) was found to be effective for the treatment of type A influenza virus infections in mice (1,(3)(4)(5). These experiments indicated that small-particle aerosols (mass median diameter, 1.4 gm) of ribavirin were more effective in reducing mortality, lesions in the lung, and virus concentrations in the lungs than approximately equivalent doses of drug given intraperitoneally (i.p.)…”

mentioning

confidence: 99%

Response of Influenza Virus-Infected Mice to Selected Doses of Ribavirin Administered Intraperitoneally or by Aerosol

Berendt

Walker

Dominik

et al. 1977

The effects of graded doses of ribavirin administered either by aerosol or intraperitoneally were compared in influenza virus-infected mice. The median effective dose values (based upon percent survival) were 3.3 and 15.8 mg/kg per day for the aerosol and intraperitoneal routes, respectively. Lung lesion scores and titer of virus were lower after aerosol than intraperitoneal therapy.Recently, ribavirin (1-3-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) was found to be effective for the treatment of type A influenza virus infections in mice (1, 3-5). These experiments indicated that small-particle aerosols (mass median diameter, 1.4 gm) of ribavirin were more effective in reducing mortality, lesions in the lung, and virus concentrations in the lungs than approximately equivalent doses of drug given intraperitoneally (i.p.) (4). However, the data did not indicate how much better aerosol administration was than i.p. in terms of dosage required to achieve the same effect, i.e., how much ribavirin was required to achieve an effective dose that would allow >50% of the mice to survive (ED50). This information would be helpful when considering the possible administration of ribavirin by aerosol for the treatment of humans, especially if a significant therapeutic advantage was gained by using the aerosol route.The objective of this research was to determine the response of influenza virus-infected mice to selected doses of ribavirin given either by aerosol or i.p.The procedures employed for housing, infecting, and treating mice [Tac:(SW)fBR] have been described by Stephen et al. (4). Four selected doses of ribavirin were administered by each route. Doses ranged from 2.5 to 20 mg/kg per day by aerosol and from 5.0 to 40.0 mg/kg per day by the i.p. route. Treatment was initiated at 6 h after exposure to the virus and was repeated daily for a total of 5 days. i.p. injections were given once daily at the same time as the aerosols. A virus control group received no treatment. The degree of gross pathology in the lungs (lung lesion score) was evaluated in three mice on day 4 and in five mice on day 7 by 1 Present address: Plum Island Animal Disease Center, P.O. Box 848, Greenport, NY 11944. methods that have been described previously (4). The concentration of virus in the lungs was also determined on day 4 by previously described methods (5). Survival was recorded daily for 21 days in 25 mice that were randomly allocated for this purpose from each treatment group. Survival data from five replicate experiments were analyzed by probit analysis (2), and the dose of ribavirin yielding 50% survival (ED50) was calculated together with 95% confidence limits. Lung lesion scores and lung virus concentration data were evaluated by analysis of variance.The results are shown graphically in Fig. 1. The ED50 values after aerosol and i.p. administration of ribavirin were 3.3 mg/kg per day (95% confidence limits, 2.5 to 4.3) and 15.8 mg/ kg per day (95% confidence limits, 12.7 and 19.5), respectively. The slopes (data not shown) for the regre...

“…Although this compound has demonstrable activity against a number of RNA viruses, its activities against viruses of the Orthomyxoviridae family have not yet been described. The related ribofuranosyl carboxamide 1-p-Dribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin) has a strong inhibitory effect on influenza A and B viruses in vitro (2,10), in animal systems (3), and in humans (5)(6)(7). It was therefore of interest to evaluate selenazofurin against influenza A and B viruses in an in vitro system.…”

mentioning

confidence: 99%

Activity of selenazofurin against influenza A and B viruses in vitro

Sidwell¹,

Huffman²,

Call³

et al. 1985

Activity of the new antiviral compound selenazofurin was compared with the known active compounds ribavirin and amantadine against influenza A and B viruses. In experiments with Madin Darby canine kidney cells, selenazofurin inhibited the cytopathic effect and yield of influenza A/NWS/33 virus, with 50% effective dose ranges of 0.7 to 1.4 micrograms/ml (virus rating [VR], 1.3 to 1.4). The 50% effective dose range for ribavirin was 1.2 to 1.6 micrograms/ml (VR, 1.0 to 1.3), and for amantadine it was 9 micrograms/ml (VR, 0.9). Selenazofurin and ribavirin were similarly inhibitory to influenza B/Lee/40 virus, whereas amantadine was inactive. Selenazofurin appeared somewhat cytotoxic in these studies at concentrations as low as 1 micrograms/ml.