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The eco-geno-toxicological impacts of the most widely used antiviral drugs against SARS-CoV2 - ribavirin, ritonavir, nirmatrelvir and tenofovir - were investigated in freshwater organisms. Ribavirin and tenofovir exhibited the highest acute toxicity in the rotifer Brachionus calyciflorus at concentrations of a few mg/L while ritonavir and nirmatrelvir showed similar effects at tens of mg/L; acute toxicity of ribavirin was also observed in the crustacean Ceriodaphnia dubia at similar concentrations. In contrast, the crustacean Thamnocephalus platyurus showed the lowest sensitivity to the antiviral drugs tested with no sublethal effects. Chronic toxicity tests revelead that these antivirals induced effects in consumers at concentrations of environmental concern (ng-µg/L). Ribavirin showed the highest toxicity to the alga Raphidocelis subcapitata, while ritonavir showed the highest toxicity to B. calyciflorus and C. dubia. DNA damage and oxidative stress were observed in C. dubia at 0.001 µg/L and 0.1 µg/L when exposed to ritonavir and nirmatrelvir respectively, and at 1 µg/L when exposed to ribavirin and tenofovir. Toxic and genotoxic environmental risks were assessed with risk quotients for ritonavir, tenofovir and ribavirin exceeding the threshold of 1, indicating significant environmental concern., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Residual antiviral drugs in wastewater may increase the risk of generating transformation products (TPs) during wastewater treatment. Therefore, chlorination behavior and toxicity evolution are essential to understand the secondary ecological risk associated with their TPs. Herein, chlorination kinetics, transformation pathways, and secondary risks of ribavirin (RBV), one of the most commonly used broad-spectrum antivirals, were investigated. The pH-dependent second-order rate constants k increased from 0.18 M -1 ·s -1 (pH 5.8) to 1.53 M -1 ·s -1 (pH 8.0) due to neutral RBV and ClO - as dominant species. 12 TPs were identified using high-resolution mass spectrometry in a nontargeted approach, of which 6 TPs were reported for the first time, and their chlorination pathways were elucidated. The luminescence inhibition rate of Vibrio fischeri exposed to chlorinated RBV solution was positively correlated with initial free active chlorine, probably due to the accumulation of toxic TPs. Quantitative structure-activity relationship prediction identified 7 TPs with elevated toxicity, concentrating on developmental toxicity and bioconcentration factors, which explained the increased toxicity of chlorinated RBV. Overall, this study highlights the urgent need to minimize the discharge of toxic chlorinated TPs into aquatic environments and contributes to environmental risk control in future pandemics and regions with high consumption of antivirals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The rapid spread of coronavirus disease 2019 has increased the consumption of some antiviral drugs, wherein these are discharged into wastewater, posing risks to the ecosystem and human health. Therefore, efforts are being made for the development of advanced oxidation processes (AOPs) to remediate water containing these pharmaceuticals. Here, the toxicity evolution of the antiviral drug ribavirin (RBV) was systematically investigated during its degradation via the UV/TiO 2 /H 2 O 2 advanced oxidation process. Under optimal conditions, RBV was almost completely eliminated within 20 min, although the mineralization rate was inadequate. Zebrafish embryo testing revealed that the ecotoxicity of the treated RBV solutions increased at some stages and decreased as the reaction time increased, which may be attributed to the formation and decomposition of various transformation products (TPs). Liquid chromatography-mass spectrometry analysis along with density functional theory calculations helped identify possible toxicity increase-causing TPs, and quantitative structure activity relationship prediction revealed that most TPs exhibit higher toxicity than the parent compound. The findings of this study suggest that, in addition to the removal rate of organics, the potential ecotoxicity of treated effluents should also be considered when AOPs are applied in wastewater treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this study., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Ribavirin has been proven to be an antiviral treatment, whereas there are still risks of hemolysis and congenital malformation. Abnormal cardiac development contributes to the occurrence and development of many heart diseases. However, there is so far no evidence that ribavirin induces human cardiac developmental toxicity. Herein, we employed the cardiac differentiation model of human induced pluripotent stem cells (hiPSCs) to determine the impact of ribavirin on heart development. Our data showed that ribavirin at clinically high concentrations (5 and 10 μM) significantly inhibited the proliferation and differentiation of hiPSCs from mesoderm to cardiac progenitor cells and cardiac progenitor cells to cardiomyocytes, but not from pluripotent status to mesoderm. Meanwhile, DCFH-DA staining revealed that ribavirin could increase ROS content in the mid-phase of differentiation. In addition, ribavirin treatment (1, 5 and 10 μM) remarkably caused DNA damage which was shown by the increase of γH2AX-positive cells and upregulation of the p53 during the differentiation of hiPSCs from mesoderm to cardiac progenitor cells. Moreover, exposuring to ribavirin (5 and 10 μM) markedly upregulated the expression of lncRNAs Gas5 in both mid-phase and late phase of differentiation and HBL1 in the mid-phase. In conclusion, our results suggest that ribavirin is detrimental in cardiac differentiation of hiPSCs, which may be associated with DNA damage, upregulated p53 and increased Gas5. It may provide the evidence for the rational clinical application of ribavirin., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Moroxydine hydrochloride (Mor) is known to have multi-antiviral activities against DNA and RNA viruses but very little information exists on its pharmacology. The paper was undertaken to explore the antiviral response and antiapoptotic mechanism of Mor against grass carp reovirus (GCRV) in Ctenopharyngodon idella kidney (CIK) cells. The results showed that exposing GCRV-infected cell to 6.3 μg mL(-1) of Mor for 96 h avoid ca. 50% apoptosis. Meanwhile, Mor had lower cytotoxicity than ribavirin (Rib) as the value of safe concentration was threefold higher than effective concentration and the compound could ensure sufficient into and out of cells within 4 h when tested at the maximal safe concentration. Mor blocked the GCRV-induced cytopathic effects and eliminated nucleocapsids in CIK cells to keep the normal morphological structure. Moreover, the expressions of viral protein genes were significantly inhibited especially the guanylyl transferase and RNA-dependent RNA polymerase related expression. Furthermore, GCRV caused Bcl-2 down-regulation and Bax mitochondrial translocation was prevented by treatment of CIK cells with Mor. The downstream effector, caspase activity was also significantly inhibited in Mor treated cells. The potential mechanism might be that mitochondrial apoptotic signals were not activated by the intervention of Mor for targeting viral gene expression. Taken together, Mor showed high anti-GCRV activity and had been proved as a secure and promising agent in viral controlling in aquaculture industry., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Ribavirin (1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a widely used broad-spectrum antiviral drug. Recently, several reports revealed genotoxic effects of ribavirin in vivo and in vitro, which were correlated with the production of reactive oxygen species (ROS). This study aimed to evaluate the genotoxicity of ribavirin and to investigate the role of the natural antioxidant silymarin to modulate this genotoxicity. Male albino mice (age, 8-10 weeks) were injected intraperitoneally (i.p.) with ribavirin at three dose levels (20, 75 and 130 mg/kg bw) either in a single injection (acute treatment) or in multiple injections on five consecutive days (sub-acute treatment). Other comparable groups were treated with silymarin (70 mg/kg bw) 1h before the injection with ribavirin. Mice were sacrificed at different sampling times (24, 48 and 72 h) after the last ribavirin treatment. Micronucleus (MN) and single-strand conformation polymorphism (SSCP) assays were used to assess genotoxic and cytotoxic effects of ribavirin and to evaluate the protective effect of the pre-treatment with silymarin. Our results reveal genotoxic and cytotoxic effects of ribavirin in the MN assay. Pre-treatment with silymarin reduced the toxicity of ribavirin. In the SSCP assay, ribavirin treatment did not induce any mutations in the two selected sites in the D-loop of mitochondrial DNA (mtDNA)., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The ability to control plant viral diseases with chemicals has great potential value for agriculture, but few chemicals are available to date due to the difficulty in obtaining effective drugs. IMP dehydrogenase is an enzyme which catalyzes the conversion of inosine 5'-monophosphate to xanthosine 5'-monophosphate in the de novo purine nucleotide synthetic pathway, and is considered a sensitive target for antiviral drugs. Two IMPDH inhibitors, tiazofurin (TR) and mycophenolic acid (MPA), were tested for their inhibitory effect on Grapevine leafroll-associated virus 3 (GLRaV-3) in in vitro grapevine explants. TR administration produced plantlets characterized by negative ELISA readings. No PCR products were obtained from these samples. This was confirmed by the absence of viral particles. MPA was essentially ineffective against GLRaV-3 replication in Sangiovese explants. This is the first report of GLRaV-3 eradication in grapevine explants following TR administration.

Ribavirin has been reported to cause error-prone replication and viral extinction in RNA viruses. The antiviral activity of ribavirin against West Nile virus (WNV) was evaluated in various cell lines to select a model in which mutagenic effects could be studied. The antiviral activity was greatest in HeLa cells as compared to CV-1, L929, Vero, or MA-104 cells. WNV was also passaged sequentially in cell monolayers treated with ribavirin to determine whether cumulative mutations could lead to viral extinction in these cell lines. The virus was abrogated in HeLa cells after 4 passages, while high viral titers persisted after many passages in other cells. A molecular clone of WNV was propagated in HeLa cells treated with 15 microg/mL ribavirin, and sequencing of viral genome segments revealed significant increases in transition mutations, demonstrating that ribavirin induced error-prone replication. The relative infectivity of viral RNA synthesized in the presence of ribavirin was shown to be reduced compared with untreated controls. These data support the hypothesis that error catastrophe is one of the modes of action for ribavirin against WNV.

Interferon (IFN)-alpha monotherapy, as well as the more effective combination therapy of IFN-alpha and ribavirin, are currently used for patients with chronic hepatitis C caused by hepatitis C virus (HCV) infection, although the mechanisms of the antiviral effects of these reagents on HCV remain ambiguous, and side effects such as anemia due to the administration of ribavirin present a problem for patients who are advanced in years. Using a recently developed reporter assay system in which genome-length dicistronic HCV RNA encoding Renilla luciferase gene was found to replicate efficiently, we found that mizoribine, an imidazole nucleoside, inhibited HCV RNA replication. The anti-HCV activity of mizoribine (IC50: approximately 100 microM) was similar to that of ribavirin. Using this genome-length HCV RNA replication monitor system, we were the first to demonstrate that the combination of IFN-alpha and ribavirin exhibited more effective anti-HCV activity than the use of IFN-alpha alone. Moreover, we found that the anti-HCV activity of mizoribine in co-treatment with IFN-alpha was at least equivalent to that of ribavirin. This effect was apparent in the presence of at least 5 microM mizoribine. Since mizoribine is currently used in several clinical applications and has not been associated with severe side effects, mizoribine is considered to be of potential use as a new anti-HCV reagent in combination with IFN-alpha.

Background/aims: Current therapies for patients with chronic hepatitis C virus (HCV) do not achieve sustained viral clearance in most patients, and are associated with severe toxic effects. Our aim was to investigate the efficacy and safety of etanercept as adjuvant to interferon and ribavirin in treatment-naive patients with HCV., Methods: Double-blind, randomized, placebo controlled trial. Fifty patients with chronic HCV were randomly assigned to receive interferon alfa-2b and ribavirin with either etanercept or placebo for 24 weeks. The main outcome measure was the absence of HCV RNA at 24 weeks, the on treatment response at the end of the etanercept randomization period., Results: At 24 weeks, HCV RNA was absent in 63% (12/19) etanercept patients compared to 32% (8/25) placebo patients (P=0.04). In addition, patients receiving etanercept had lower frequency of most adverse events categories compared to placebo., Conclusions: Etanercept given for 24 weeks as adjuvant therapy to interferon and ribavirin significantly improved virologic response at the end of the etanercept randomization period among patients with HCV, and was associated with decreased incidence of most adverse effects associated with interferon and ribavirin.

Tiazofurin (TZF) is a cytostatic drug that leads to depletion of the GTP pool in tumor and normal cells via its active metabolite tiazofurin-adenine dinucleotide (TAD). TAD was detected in different cell lines, but not in erythrocytes, so the mechanism of erythrocytotoxicity of TZF remains unclear. The purpose of this study was to evaluate in vitro and in vivo action of tiazofurin on rat erythrocytes (RBC). After two decades of clinical trials the question of erythrocytotoxicity of TZF had remained unexplained making this study justified. Since we have previously demonstrated early erythrocytotoxic effects in male Wistar rats, we extend this finding on isolated RBC. Isolated erythrocytes from untreated animals were treated in buffered solution or plasma containing TZF. In addition, groups of 10 rats were treated with 200 and 1000 mg/kg of TZF and hematologic parameters were analyzed by flowcytometry and by the analysis of the peripheral blood smears. Early signs of hemolysis or aberrant structures were monitored by scanning probe microscopy (SPM). We suggest that correlation exists between early erythrocytotoxicity and irregularities in erythrocyte morphology and membrane integrity. We also found that TZF affects responsiveness to oxidative stress. This is in concordance with flowcytometric findings describing anisocytosis and anisochromosis of RBC.

The genotoxic and cytotoxic effects of the antiviral drug, ribavirin, was studied in rat bone marrow by employing the micronucleus assay. Ribavirin in doses of 10, 15, 20, 30, 50, 75, 100 and 200 mg/kg, and cyclophosphamide (CP) 40 mg/kg (only for sex-difference study) were injected intraperitoneally. Bone marrow was collected at 24 h and 48 h following the injection. To evaluate the recovery, the bone marrow was also sampled at 72 h from 20, 100 and 200 mg/kg treated rats. The micronucleus assay was conducted according to the standard procedure. Ribavirin elevated the incidence of micronuclei (except 10 mg/kg) in erythrocytes (P<0.01). The micronucleated polychromatic erythrocytes showed the initial steep increase at 15 and 20 mg/kg dose level, then with the gradual increase, possibly due to the limited metabolism and action of higher doses. The incidence of micronucleated normochromatic erythrocytes was not dose dependent. The effect was more at 48 h than 24 h due to prolonged toxicity of the drug or its metabolites, and by 72 h, recovery was observed even though the genotoxicity was significant. The PCE% decreased as the dose was increased up to 75 mg/kg, then without much difference between two higher doses. Only 100 mg/kg ribavirin and CP showed more toxicity on male rats. Cytotoxicity was seen due to hindered erythropoiesis or cell destruction. Our findings suggest that ribavirin is genotoxic and cytotoxic agent for rat bone marrow.

Thirty-nine hemophiliac patients, negative for human immunodeficiency virus, with chronic hepatitis C who failed to respond to interferon (IFN) at 3 million units (MU) given subcutaneously thrice weekly for at least 3 months were retreated with 5 MU IFN for 6 months followed by 3 MU IFN in combination with daily oral doses of 1 or 1.2 g ribavirin. Thirty-four patients (87%) completed the study. In 4 patients treatment was discontinued because of treatment-related symptoms; 1 patient dropped out. Dosage reduction was required in 10 patients (26%) because of ribavirin-related anemia or IFN-related side effects. By intention-to-treat analysis, 14 (37%) had a sustained virologic response with preference for those infected by genotypes other than type 1 (43% versus 12%) and with high transaminases levels (168 U/L versus 116 U/L). Thus, IFN and ribavirin combination therapy led to a sustained suppression of hepatitis in one third of hemophiliac patients resistant to conventional monotherapy.

Ribavirin (1-beta-D-ribofuranosyl-1,2,4, triazole-3 carboxamide) is a broad-spectrum antiviral drug. This study was aimed to investigate the mutagenicity of ribavirin on germ cells by employing sperm morphology assay. Male Wistar rats were treated with water, cyclophosphamide (CP) 40 mg/kg, and ribavirin 20, 100 and 200 mg/kg (i.p.) for 5 consecutive days at intervals of 24h. Following the last exposure, at 14, 28, 35, 42 and 70 days, the epididymal sperm smears were obtained and stained according to the standard procedure. One thousand sperms per animal were classified into normal and different abnormal types. Both CP and ribavirin-induced anomalies of head and tail of sperm except at 70 days. In CP groups, maximum incidence was observed at 28, 35 and 42 days. Ribavirin 20 mg/kg induced maximum incidence at 14 and 42 days, 100 mg/kg at 28 and 42 days and 200 mg/kg at 28-42 days. These results show that ribavirin is mutagenic to rat germ cells in a transient fashion.

In this study hematological toxicity was analyzed after the single and repeated applications of tiazofurin (TZF). Cellularity of bone marrow, spleen and peripheral blood was examined, spanning the period of fifty days after the initial application. Analysis of hematological parameters was performed by slightly modified conventional techniques. The fraction of erythroid series was monitored during the experiment. Presented data describe kinetics of damage and recovery of hemopoietic tissue. Our results indicate that the effect of tiazofurin on cellularity of bone marrow and spleen and on erythropoiesis is reversible and dose dependent within tested dose range and therapeutic regimes. Twenty days after the application normal function of hemopoietic tissues was restored. This approach and results can be useful in defining the timing for sequencing and combination therapy with tiazofurin.

We studied the effects of two antiviral agents, human interferon-alpha (IFN-alpha) and ribavirin, on subacute sclerosing panencephalitis (SSPE) virus infections in hamsters. By intracranial administration, IFN-alpha alone improved the survival of infected hamsters by 20% at a dose of 6 x 10(4) IU/kg every other day for 10 days. When the dose of IFN-alpha was increased incrementally to 6 x 10(6) IU/kg, the survival rate increased by 70% in a dose-dependent manner. The combination of IFN-alpha and ribavirin had a synergic inhibitory effect on the replication of SSPE virus in cell culture. Combination of IFN-alpha (at a dose of 6 x 10(5) IU/kg) with ribavirin (at a dose of 1 mg/kg) completely prevented mortality. This was significantly better than either IFN-alpha or ribavirin monotherapy (p < 0.05). Under the conditions used, IFN-alpha did not enhance the toxicity of ribavirin in hamsters. Intraventricular administration of high dose IFN-alpha and ribavirin may have potential usefulness in the treatment of patients with SSPE.

Sandfly fever Sicilian virus (SFSV) was used in our laboratory to screen antiviral substances active toward viruses of the Bunyaviridae family. Antiviral activity was estimated by the reduction of the cytopathic effect of SFSV on infected Vero cells. Cytotoxicity was evaluated by determining the inhibition of Trypan blue exclusion. The specificity of action of each tested compound was estimated by the selectivity index (CD50/ED50). Selectivity indices of human recombinant interferon-alpha (IFN alpha) (Roferon and Introna), iota-, kappa- and lambda- carrageenans, fucoidan and 6-azauridine were much higher than that of ribavirin, the only antiviral substance which has been previously investigated for its inhibitory effects on Phlebovirus infections. Other compounds showed significant antiviral activity: glycyrrhizin, suramin sodium, dextran sulphate and pentosan polysulphate. All these compounds caused a concentration-dependent reduction in the virus yield. Ribavirin, 6-azauridine and IFN alpha have been shown to inhibit a late step of the virus replicative cycle, whereas glycyrrhizin and suramin sodium were active at an early step and the sulphated polysaccharides inhibited adsorption of SFSV on the cells. The antiviral compounds selected in this study as specific inhibitors of in vitro replication of SFSV are promising candidates for the chemotherapy of haemorrhagic fevers caused by viruses of the Bunyaviridae family. The combination of IFN alpha and ribavirin, which showed a synergistic antiviral effect, should be evaluated for the treatment of these infections.

A multiwell tissue culture system was developed to study the influence of various substances on hepatitis A virus (HAV) propagation. A panel of 20 substances of different structure types, each with known effect against at least some viruses, was studied at a concentration of 100 microM. Three substances showed reproducible inhibition. The strongest inhibitor, arabinosylcytosine, also produced cytotoxic changes in cells down to a concentration of 1 microM, and its effect was considered as nonspecific. Amantadine and ribavirin showed a moderate effect at 100 microM. A stronger inhibition was seen at 250 and 500 microM, doses that are toxic and impractical for clinical use. Although no promising candidates for antiviral treatment of hepatitis A have emerged from the present study, the assay model described here would seem useful in the screening of substances with inhibitory effects on HAV.

The toxicity of anti-HIV drugs, 3'-azido-3'-deoxythymidine (zidovudine, AZT), 2',3'-dideoxycytidine (DDC), 2',3'-dideoxy-2',3'-didehydrothymidine (d4T) and ribavirin was studied in vitro in murine fetal liver cells (FLC) and in bone marrow cells. These studies indicate that d4T is the least toxic drug and ribavirin is the most toxic agent in both models. However, the murine FLC system was found to be a more sensitive model for the assessment of toxicity of anti-HIV agents towards erythroid progenitor cells as indicated by the IC50 values.

Ribavirin, a new synthetic antiviral agent, was studied for dominant lethal effects in male CD rats. The drug was administered intraperitoneally at doses of 50, 100 and 200 mg/kg/day for 5 days. Males were mated weekly with 8 consecutive batches of female rats. Marginal increase in early foetal death detected in Assessment Weeks 3 and 8 in females mated with the low-dose and high-dose males were not dose-related and were most probably chance events caused by the particularly low vehicle control frequencies for these 2 weeks. Also, the slightly reduced pregnancy proportion among females mated with the high-dose treated males was to a substantial extent the effect of a single male rate which failed to fertilize any females. Ribavirin was, therefore, regarded as being devoid of any mutagenic potential demonstrable by a rat dominant lethal assay.

Ribamidine (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine) was inhibitory in rhesus monkey kidney (LLC-MK2 derivative) cells to Adames and Balliet strains of Punta Toro virus (PTV), a Phlebovirus related to Rift Valley fever and sandfly fever viruses. The 50% effective dose was 8 and 12 micrograms/ml against each respective virus strain; the 50% cytotoxic dose was 320 micrograms/ml, giving selectivity indices of 40 and 27 against each virus strain. The virus ratings were 1.2 and 1.0, respectively. In radiolabel uptake studies, ribamidine had a moderate effect on [3H]leucine uptake at dosages down to 1 microgram/ml, but [3H]thymidine, [32P], and [3H]uridine were inhibited at high (100-1000 micrograms/ml) doses only. Subcutaneous (s.c.) and oral treatments of Adames PTV-infected mice were equally highly effective, as evidenced particularly by 100% survivors. Reduced hepatic icterus, serum oxalic acid transaminase, serum glutamic pyruvic acid transaminase, and recoverable virus titers from livers and sera of infected mice were also seen as a result of ribamidine treatment. Twice daily treatment for 5 days could be started as late as 72 h post-virus inoculation (p.v.i.) with significant inhibition of PTV infection seen. Single s.c. treatments administered as late as 48 h p.v.i. were similarly effective. Using the chronic therapy schedule, the maximum tolerated dose was 1000 mg/kg/day and the minimum effective dose was 31.3 to 62.5 mg/kg/day. Using single treatment, a maximum tolerated dose was greater than 1000 mg/kg, and the minimum effective dose was 125 mg/kg. Ribamidine s.c. treatment of mice infected intracerebrally with the Balliet strain of PTV resulted in a moderate infection-inhibitory effect, seen especially by reduced virus titers in the brains of the infected, treated mice.

The micronucleus test and mitotic chromosome analysis were used to study the in vivo mutagenic activity of ribavirin on bone marrow cells of Swiss albino mice. To determine the incidence of micronuclei, mice were injected i.p. twice, at an interval of 24 h. with the drug at doses of 20, 100 and 200 mg/kg. Animals were killed 6 h after the second dose and bone marrow was examined for the presence of micronuclei in developing erythrocytes. Ribavirin significantly (P less than 0.05) induced micronuclei in polychromatic erythrocytes at all doses. A study was conducted to investigate the cytogenetic effect of the drug on mitotic chromosomes. Ribavirin at 200 mg/kg/day was administered to mice for 3 and 5 days. Repeated treatment with the high dose of ribavirin produced a highly significant (P less than 0.02) increase in abnormal metaphase spreads. The results indicate that ribavirin is mutagenic to bone marrow cells of mice as evaluated by the micronucleus test and by chromosome analysis.

3-Nitro-3-deazauridine (3N-3DU) is a new synthetic nucleoside having activity against members of 5 RNA virus families including: paramyxoviruses (parainfluenza, PIV), picornaviruses (rhino-, RV), rhabdoviruses (vesicular stomatitis, VSV), togaviruses (Semliki Forest, SFV) and bunyaviruses (Punta Toro, PTV). In this report, we evaluate and compare its activity with the parent nucleoside, 3-deazauridine (3DU) and ribavirin as drug standards. Comparison of drug activities utilizes observations of antiviral indices, which are determined by the following formula: maximum tolerated dose (MTD)/minimum inhibitory concentration (MIC). The antiviral index (AI) of 3N-3DU (AI 15.3) was comparable to ribavirin and much higher than 3DU when evaluated against PIV. The 3N-3DU was the most active of the three when tested against RV (AI 24.1), SFV (AI 76.9) or VSV (AI 50). In contrast to the RV activity, 3N-3DU (AI 0.5) and 3DU (AI less than 0.1) were less active than ribavirin (AI 1.3) when evaluated against poliovirus, type 1 (PoV). Ribavirin (AI 10.0) was more active than 3N-3DU (AI 2.4) and 3DU (AI less than 0.1) against PTV. 3N-3DU exhibited comparable toxicity to ribavirin in KB cells, was 4-fold less toxic in WISH cells and 4-fold more toxic in LLC-MK2 cells. Overall, 3N-3DU is markedly less toxic than its parent nucleoside, 3DU. It appears from this study that the structural modification of 3DU resulting from the addition of the nitro group in the 3 position of the base reduces toxicity and enhances the antiviral activity.