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At least 19 recordsLinked to original sources
PubMed1979

Ribavirin treatment in murine autoimmune disease. I. Therapeutic efficacy and effect on the immune response.

NZB/W F1 female mice were treated from 20 weeks of age with ribavirin (a broad spectrum antiviral drug), cyclophosphamide, or saline. Treatment with ribavirin (250 mg/kg twice weekly) prolonged survival from 9.8 to 18.5 months, reduced anti-DNA antibodies, and prevented proteinuria. Ability of ribavirin to prolong survival was dose related when given on a twice weekly schedule. However, daily ribavirin (25 mg/kg/day) was as effective as higher intermittent doses. Optimal ribavirin therapy was equal to cyclophosphamide treatment with regard to prolongation of survival. Ribavirin treatment did not significantly alter the body weight, hematocrit, WBC count, serum immunoglobulins, or Coombs reactivity. No alterations in either cellular or humoral immune responses were noted in NZB/W F1 or BALB/c mice treated for prolonged periods with ribavirin. The impressive therapeutic response to a broad spectrum antiviral agent seen in mice already manifesting immune complex nephritis provides a new therapeutic approach to the treatment of autoimmunity.

Animals↗
PubMed1979

Mechanism and specificity of action of ribavirin.

Ribavirin at a concentration of 30 mug/ml added immediately after infection completely inhibited influenza A/Port Chalmers/1/73 (H(3)N(2)) virus hemagglutinin production in infected MDCK cells. Under these conditions, host cell protein synthesis was inhibited by only 10 to 20%. Polyacrylamide gel electrophoresis of [(35)S]methionine-labeled material from virus-infected cultures confirmed that ribavirin inhibited viral but not host cell protein synthesis. In parallel experiments, actinomycin D also preferentially inhibited viral protein synthesis. The possibility that ribavirin inhibited viral protein synthesis as a result of general inhibition of ribonucleic acid synthesis was therefore examined. In uninfected cells, ribavirin at 30 mug/ml inhibited the incorporation of [(14)C]inosine or [(3)H]uridine into ribonucleic acid but stimulated the incorporation of [(3)H]guanosine. The effects noted are consistent with an inhibition of the host cell enzyme inosine 5'-monophosphate dehydrogenase. This suggestion is supported by the finding that addition of guanosine, but not inosine, to the culture medium substantially reversed the antiviral effect of ribavirin. There was no separation between the concentration of ribavirin causing inhibition of influenza A viral protein synthesis or inhibition of MDCK cell ribonucleic acid synthesis, suggesting that ribavirin is not specifically antiviral in this system but inhibits viral protein synthesis as a result of the general inhibition of ribonucleic acid synthesis.

Animals↗
PubMed1975

In vitro and in vivo effect of 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin) on types 1 and 3 parainfulenza virus infections.

1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin) had significant in vitro activity against type 1 parainfluenza (Sendai) and type 3 parainogenic (HA-1) viruses. Activity was manifested as inhibition of both viral cytopathogenic effect and of recoverable virus or viral hemagglutinin titer. The minimum Sendai virus inhibitory concentration was determined to be approximately 3.2 mug/ml. Previous studies had determined the minimum concentration inhibiting HA-1 virus was approximately 1-10 mug/ml. The effect of time of addition of ribavirin to virus-infected cells was determined; maximal activity was seen when the drug added just prior to either virus or within 4-8 h after each virus, although anti-Senadi viral effects were still apparent when ribavirin was added as late as 24 h after the virus. Ribavirin had no effect on adsorption of HA-1 or Sendai virus to cells. Lethal Sendai virus infections of mice were significantly inhibited by multiple intraperitoneal ribavirin treatment, starting either 4 h before or up to 24 h after virus inoculation. Therapy starting 48, 72 or 96 h after virus exposure had a moderate degree of efficacy. Treatment using an aerosol chamber also was of moderate effectiveness, although the procedure was considered traumatic to the animals. A nonlethal, principally upper respiratory tract infection of hamsters induced by the HA-1 virus was inhibited by ribavirin therapy. Treatment administered intraperitoneally, per os or by aerosol chamber resulted in reduced 23-day antibody titers to the virus, presumably because of reduction of virus in the animal. In a separate experiment, intraperitoneal ribavirin therapy resulted in a 1 log10 or less reduction in virus titer in nasal washings from HA-1 virus-infected hamsters, whereas, when the drug was administered intranasally in a dry powder aerosol spray, nasal virus titers were reduced up to 2 log10 and a moderate virus-induced lung consolidation was completely inhibited.

Adsorption↗
PubMed1979

Studies on the mechanism of antiviral action of 1-(beta-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (ribavirin).

Syntheses are described for the 5'-phosphates of the 2'- and 3'-O-methylribavirins (2a and 2b) and the methyl ester of ribavirin 5'-phosphate (3). The 5'-phosphate of 1-beta-(D-ribofuranosyl)-1,2,4-triazole (2d) was obtained via the 3-carboxyl derivative of ribavirin 5'-phosphate (2c). Compounds 2a, 2b, and 2d were inactive as inactive as inhibitors of IMP dehydrogenase under conditions where the parent ribavirin 5'-phosphate (2) was an effective inhibitor. Weak inhibitory activity was exhibited by 3 (Ki approximately 200 muM) and 2c (K1 approximately 70 muM). Under conditions where ribavirin (1) is effectively phosphorylated by rat liver nucleoside kinase, the 2'- and 3'-O-methylribavirins (1a and 1b), the 3-carboxylate of ribavirin (1c), and the riboside of 1,2,4-triazole (1d) were totally inactive. The overall results are fully consistent with the lack of antiviral activity of 1a and 1b, while the specificity of ribavirin as an antiviral agent is further underlined by the behavior of the methyl ester 3.

Animals↗
PubMed1976

Comparative clinical and laboratory evaluation of the prophylactic capacity of ribavirin, amantadine hydrochloride, and placebo in induced human influenza type A.

The comparative prophylactic effectiveness of oral treatment with ribavirin (1-beta-D-ribofuranosyl-1,2,4,triazole-3-carboxamide; virazole) and amantadine hydrochloride against artificially induced infection with influenza A virus was evaluated in 29 seronegative men who received ribavirin capsules (200 mg) three times daily, placebo capsules three times daily, or amantadine capsules (100 mg) twice daily. Medication was started two days before the inoculation of 2 X 10(4) 50% tissue culture infective doses of A University of Maryland/2/74 (H3N2) influenza virus and was continued for eight days after challege. Nine of the 10 subjects who received ribavirin, eight of the nine subjects who received placebo, and six of the 10 subjects who received amantadine developed influenzal illness. Significantly less virus was isolated from the amantadine-treated group than from the placebo-treated or the ribavirin-treated group. Antibody responses of the ribavirin-treated and placebo-treated groups were quite similar to each other; however, prophylactic treatment with amantadine significantly reduced titers of serum antibody and febrile responses. In a separate clinical trial involving challenge with A/Dunedin/73 (H3N2) influenza virus, ribavirin also failed to show prophylactic effectiveness.

Adult↗
PubMed1977

Aerosol therapy of influenza infections of mice and primates with rimantadine, ribavirin, and related compounds.

Ribavirin administered as small-article aerosols had significant therapeutic effect in the treatment of viral respiratory infections induced by influenza virus. The preliminary experiment using ribavirin to treat influenza infection in the squirrel monkey is encouraging. We expect to extend these experiments by initiating therapy at a later time to investigate the potential value of ribavirin in a clinical situation. Several derivatives of ribavirin are effective antiviral compounds. The tri-O-acetyl derivative appears to offer a potential advantage over ribavirin, although this cannot be stated with certainty since the data were obtained from separate experiments. Radiolabeling has been used as a means of measuring tissue concentration and clearance rates of various drugs. It is hoped that the use of labeled ribavirin and the tri-O-acetyl derivative will assist us in determining whether a depot of antiviral drug is created in pulmonary tissues after administration as a small-particle aerosol. These experiments are now in progress.

Adamantane↗
PubMed1992

Ribavirin mitigates wart growth in rabbits at early stages of infection with cottontail rabbit papillomavirus.

The challenge to develop antiviral agents effective against DNA viruses such as human papillomavirus (HPV) has been dependent on finding an animal model which mimics the human forms of the disease. We have used an existing model system for the purpose of measuring the effect of antiviral drugs on the inhibition of growth of these lesions. This was based upon domestic rabbits which efficiently grow cutaneous papillomas (warts) when infected with cottontail rabbit papillomavirus (CRPV). One agent which had shown significant success in achieving these goals was ribavirin. Ribavirin was administered intradermally shortly prior to infection at multiple sites with CRPV. Following daily injections of this drug for eight weeks, we have shown a dose-dependent response which had markedly reduced the number of warts, the time of first appearance of warts and reduced the tumor mass as compared to placebo-treated control animals. At the highest dose of ribavirin tested, 30 mg/kg/day, compared to controls, the average reduction in the number of warts was 52%, the average time of first appearance of warts was 49% longer, and the average mass of the warts was reduced by 98%. No detectable antibodies to CRPV were observed in any of the animals. The only side effects which were observed was focal alopecia, and a decrease in body growth upon prolonged treatment, both of which were completely reversible. Pharmacokinetic studies established the metabolism of ribavirin over a 24-h period of time. Ribavirin administered beginning 12 or 30 days post-infection, while not reducing the number of warts, slightly retarded the growth of warts as determined by date of first appearance of warts and mass of warts.

Animals↗
PubMed1978

Adenosine kinase initiates the major route of ribavirin activation in a cultured human cell line.

Inhibition of IMP dehydrogenase (EC 1.2.1.14) by ribavirin causes the normal human lymphoblast to excrete increased amounts of newly formed purine into the culture medium. In order for ribavirin to be active as an inhibitor of the dehydrogenase, this synthetic nucleoside must be phosphorylated. The effect of ribavirin on purine excretion has been determined with a normal lymphoblast line, and with lymphoblast lines deficient in hypoxanthine phosphoribosyltransferase (IMP:pyrophosphate phosphoribosyl-transferase, EC 2.4.2.8), in adenosine kinase (ATP:adenosine 5'-phosphotransferase, EC 2.7.1.20), and in both hypoxanthine phosphoribosyltransferase and adenosine kinase. Resistance to the effect of ribavirin on purine excretion was associated only with those cell lines deficient in adenosine kinase activity. These cell lines have normal deoxyadenosine kinase (ATP:deoxyadenosine 5'-phosphotransferase, EC 2.7.1.76) activity. Therefore, the nucleoside kinase activity responsible for ribavirin phosphorylation is adenosine kinase.

Adenosine Kinase↗
PubMed1977

Effects of small-particle aerosols of rimantadine and ribavirin on arterial blood pH and gas tensions and lung water content of A2 influenza-infected mice.

The respiratory pathophysiology of A2 influenza infection was studied in mice treated with small-particle aerosols (SPA) of rimantadine or ribavirin. Untreated infections in mice resulted in survival rates of 15% or less and were characterized by (i) severe hypoventilation (decreased P(O2) and increased P(CO2)), (ii) compensated respiratory acidosis (increased P(CO2) and HCO(3) (-), with normal pH), (iii) pneumonia with increased ratio of wet/dry lung weight, and (iv) hypothermia. Treatment with SPA of rimantadine (21 mg/kg per day for 4 days) beginning 72 h after virus challenge significantly improved survival rate (80%) but failed to alter lung pathology from that found in infected, untreated mice. Rimantadine treatment decreased somewhat the severity of hypoventilation, respiratory acidosis, lung wet weight, hypothermia, and lung virus titers from that observed in infected, untreated mice. SPA of ribavirin (26 mg/kg per day for 4 days) initiated 6 h after SPA exposure of mice to virus significantly improved survival rate (95%) and reduced lung virus titers and lung pathology. Gas exchange and pulmonary edema in ribavirin-treated, infected mice were significantly improved over those of infected, untreated controls. The mechanisms for increased survival rates induced by SPA of rimantadine remain uncertain, since increased survival rates could not be ascribed entirely to improvements in lung functions. In contrast, however, ribavirin treatment appeared to improve survival rates by reducing major lung pathology and pulmonary dysfunction. This was probably mediated through the antiviral effects of ribavirin.

Adamantane↗
PubMed1977

Double-blind evaluation of oral ribavirin (Virazole) in experimental influenza A virus infection in volunteers.

The prophylactic effectiveness of oral administration of ribavirin (1-beta-d-ribofuranosyl-1,2,4-triazole-3-carboxamide) against experimentally induced influenza A infection was evaluated in a double-blind clinical trial in normal volunteers. Fourteen men received ribavirin capsules (1,000 mg/day in four divided doses) and 15 other men received identical-appearing placebo capsules beginning 6 h after the intranasal inoculation of 3.4 log(10) 50% tissue culture infectious doses of influenza virus A/Victoria/3/75 H3N2 and continuing for 5 days after challenge. The total number of moderate-to-severe symptom scores and the total number of temperatures >/=100 degrees F (37.8 degrees C) were significantly lower in the ribavirin group compared with the placebo group. The mean quantity of virus shed in nasal wash specimens and the total number of days that there were viral titers greater than 1.0 log(10) 50% tissue culture infectious doses per ml were significantly greater in the placebo group. There was no difference between the frequencies of virus isolated or the antibody responses in the two groups. Therefore, prophylactic ribavirin ameliorated symptoms and fever indicative of moderate-to-severe illness, but had no effect on the manifestations of mild illness in response to influenza A challenge. A transient rise in total serum bilirubin occurred in 29% of the ribavirin-treated volunteers and in none of the placebo-treated volunteers.

Adult↗
PubMed1992

Respiratory syncytial virus and ribavirin: quo vadis?

Respiratory syncytial virus is the major respiratory pathogen in infants and young children. Every year, this unique and ubiquitous virus accounts for substantial morbidity and occasional mortality in this age group. Until recently, therapy for respiratory syncytial virus infections was limited to supportive measures such as hydration, supplemental oxygen, and assisted ventilation. Therefore, the licensure of ribavirin in 1986 for treatment of respiratory syncytial virus infections raised hopes for specific and effective therapy. However, the use of ribavirin has been the subject of continuing controversy and debate. Despite at least eight controlled clinical trials involving collectively over 170 patients treated with ribavirin since 1983, no clear consensus has developed regarding which patients should be treated with ribavirin. Major issues are weaknesses in the design and methodology of studies that claim treatment efficacy, the clinical significance of the demonstrated treatment effects, potential teratogenicity to health care workers exposed to aerosolized ribavirin, and cost-effectiveness of the intervention. This review will explore each of these areas of controversy and consider the unanswered questions to which future research must be directed.

Animals↗
PubMed1976

Effect of ribavirin on murine cytomegalovirus infection.

Ribavirin (1-beta-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, ribavirin was ineffective in the treatment of both acute and chronic murine cytomegalovirus infections.

Acute Disease↗
PubMed1977

Inhibition of influenza virus ribonucleic acid polymerase by ribavirin triphosphate.

Ribavirin 5'-triphosphate (RTP), derived from the broad-spectrum antiviral compound ribavirin (Virazole), can selectively inhibit influenza virus ribonucleic acid polymerase in a cell-free assay. Ribavirin and its 5'-monophosphate have no effect on the polymerase. The inhibition is competitive with respect to adenosine 5'-triphosphate and guanosine 5'-triphosphate. RTP also inhibits ApG- and GpC-stimulated influenza virus ribonucleic acid polymerase. Since ribavirin is phosphorylated in the cell, the inhibition of influenza multiplication in the cell may also be caused by RTP.

DNA-Directed RNA Polymerases↗
PubMed1976

Theoretical studies of the conformational properties of ribavirin.

One of the factors required for the antiviral activity of the synthetic nucleoside, ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), is the ability of the molecule to adopt the substrate conformation specified by the enzyme for which it is a competitive inhibitor, inosine 5'-phosphate dehydrogenase (IMP:NAD+ oxidoreductase, EC 1.2.1.14). The calculated glycosidic minimum for ribavirin is the high syn conformation, which is in agreement with experimental determinations of the molecule's solution conformation. The similarity in solution between the conformation of the active ribavirin molecule and the conformation of its inactive 5-methyl and 5-chloro derivatives indicate that some other substrate conformation is specified by the enzyme. The high anti conformation, found by these calculations to be close in energy to the high syn minimum, is postulated to be the active conformation required by the enzyme. The inactivity of the 5-methyl and 5-chloro derivatives is attributed to the much greater stability of these derivatives in the inactive high syn conformation.

Binding Sites↗
PubMed1976

Double-blind clinical assessment of ribavirin (virazole) in the prevention of induced infection with type B influenza virus.

The prophylactic effectiveness of oral administration of ribavirin (1-beta-D-ribofuranosyl-1,24-triazole-3-carboxamide, virazole) against artificially induced influenza B infection was evaluated in a double-blind clinical trial. Fifteen seronegative men received ribavirin capsules (600 mg/day in three divided doses), and 15 other men received placebo capsules two days before the inoculation of 6.4 X 10(4) 50% tissue culture infective doses of influenza virus B/Georgia/26/74 and for eight days after challenge. Ten men (69%) in each of the two groups developed mild to severe influenzal illness. Of these, five placebo-treated men developed severe febrile illness, while only one drug-treated man had illness of comparable severity. Illness of moderate severity was observed in three placebo-treated conrols and two drug recipients. There was no difference between the frequencies of isolation of virus or the anitbody responses in the two groups. Ribavirin suppressed signs and symptoms induced by influenza B challenge, but its effectiveness was marginal.

Adult↗
PubMed1977

Comparison of the development of resistant strains of Type 1 herpes simplex virus to in vitro antiviral activity of 5-iodo-2'-deoxyuridine or ribavirin.

Exposure of HSV/1 to low concentrations of ribavirin during 4--5 passages does not produce ribavirin-resistant virus. IDU resistance was developed by HSV/1 while it was being passed simultaneously. This resistance was seen to develop in both KB and Vero cells. The IDU-resistant virus is also resistant to ribavirin in KB cells.

Drug Resistance, Microbial↗
PubMed1978

Reversible inhibition of cellular metabolism by ribavirin.

The broad spectrum antiviral drug ribavirin (Virazole, 1-beta-d-ribofuranosyl-1,2,4-triazole-3-carboxamide) inhibits cellular macromolecular synthesis as well as cell division in eucaryotic cells. The concentration and time dependence have been studied. One-hour treatment with 25 muM ribavirin or 18 h with 2 muM inhibited the deoxyribonucleic acid synthesis to 50%. Higher concentrations of ribavirin were required to obtain a similar inhibition of ribonucleic acid and protein synthesis. This effect on cell metabolism and cell division can be reversed by removing the drug from the cells.

Cell Division↗
PubMed1979

Effects of ribavirin on BHK-21 cells acutely or persistently infected with mumps virus.

The effects of ribavirin on BHK-21 cells acutely infected with mumps virus were compared to the effects of the drug on the same cell line persistently infected with mumps virus. Visible cytotoxicity was minimal for both cell types; however, there was an inhibition of cell replication with increasing drug concentrations. Ribavirin had marked antiviral activity against both the acute and persistent infections as determined by an inhibition of hemadsorption plaque formation, decreased immunofluorescence, and a reduction in the release of infectious virus. Even after the drug had been on the persistently infected cells for 72 h, there was still antigen production detectable by immunofluorescence, although the cells no longer hemadsorbed chicken erythrocytes. Ribavirin removal from both types of infection resulted in the renewed synthesis of virus.

Animals↗