Hematological and bone marrow effects of ribavirin in rhesus monkeys

Canonico, Peter G.; Kastello, Michael D.; Cosgriff, Thomas M.; Donovan, Janet; Ross, Paul E.; Spears, Charles T.; Stephen, Edward L.

doi:10.1016/0041-008x(84)90139-x

Cited by 46 publications

(19 citation statements)

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“…3), but it resolved promptly and consistently on withdrawal of drug therapy. Rhesus macaques have been shown to be particularly sensitive to the erythrotoxic effects of ribavirin, to an extent greater than that seen in humans (2,21). While the short-term impact on bone marrow in these animals can only be inferred from peripheral hematological studies, histopathological findings conducted up to 5 months following therapy revealed no long-term adverse effects.…”

Section: Discussionmentioning

confidence: 93%

“…Thrombocytosis is a recognized side effect of ribavirin administration in rhesus macaques (and, to a lesser extent, in humans) (2). The mechanism for this phenomenon is undefined; however, an increase in megakaryocyte number and ploidy in ribavirin-treated macaques suggests that there is a stimulus to production (T. M. Cosgriff, P. G. Canonico (23).…”

Section: Discussionmentioning

confidence: 99%

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Ribavirin prophylaxis and therapy for experimental argentine hemorrhagic fever

McKee

Huggins

Trahan

et al. 1988

Antimicrob Agents Chemother

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Junin virus-infected rhesus macaques received prophylactic and therapeutic ribavirin to assess the potential of this drug for treating humans with Argentine hemorrhagic fever. When ribavirin was administered intramuscularly at the time of experimental infection with the lethal P3790 strain of Junin virus, all animals were protected from clinical disease. A delay in the initiation of therapy until after the onset of illness resulted in improvement and resolution of systemic signs of disease; however, survivors subsequently developed a late-onset central nervous system infection which was fatal in two of three animals. Side effects of ribavirin included thrombocytosis and severe anemia, both of which resolved promptly on withdrawal of drug therapy. Results of this study suggest that ribavirin may prove useful in treating humans with Argentine hemorrhagic fever.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Ribavirin prophylaxis and therapy for experimental argentine hemorrhagic fever

McKee

Huggins

Trahan

et al. 1988

Antimicrob Agents Chemother

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“…11 In Rhesus monkeys treated with RBV, anemia was shown to be caused by an increased rate of erythrocyte removal and predominantly followed the erythrophagocytic extravascular type. 21 The modifications that induced erythrocyte phagocytosis had not been investigated in detail in either animals or patients treated with RBV.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous report, in RBV-treated monkeys, erythrophagocytosis by bone marrow macrophages, as well as accumulation of granular pigment and erythrocyte remnants in liver, spleen, and bone marrow phagocytes have been observed, with no evidence for intravascular erythrocyte destruction. 21 Therefore, we hypothesized that RBV may be responsible for membrane oxidative damage, which promotes a premature extravascular red cell removal similar to what was observed in congenital erythrocyte diseases, such as thalassemic syndromes, sickle cell disease, and G6PD deficiency. [22][23][24] We tested this hypothesis in vitro by evaluating indicators of erythrocyte oxidative susceptibility, such as hexosemonophosphate shunt (HMS) and in vivo by studying red cell features of a group of HCV patients undergoing RBV or RBV ϩ IFN administration.…”

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confidence: 99%

Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: Role of membrane oxidative damage

et al. 2000

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The antiviral drug ribavirin (RBV) is widely used in combination with interferon (IFN) in the treatment of chronic hepatitis C virus (HCV) infection. A major side effect of RBV is a reversible hemolytic anemia. We have evaluated the in vitro effects of RBV on erythrocyte adenosine triphosphate (ATP) content and on hexosemonophosphate shunt (HMS). The ATP levels were significantly decreased in the presence of RBV and the HMS was increased, suggesting the presence of red cell susceptibility to oxidation. In vivo, we have studied the hematologic effects of treatment with RBV alone or in combination with IFN in 11 patients with chronic hepatitis C: 6 were treated with RBV (1,000-1,200 mg/d) and 5 were treated with a combination of RBV and IFN (5 million U thrice weekly). Patients were studied at semi-monthly intervals from 0 to day 60 of therapy. Both treatments were associated with a significant reduction in hemoglobin levels (steady state level at day 45) and a marked increase in absolute reticulocyte counts. Erythrocyte Na-K pump activity was significantly diminished, whereas K-Cl cotransport and its dithiotreitol-sensitive fraction, malondialdehyde and methemoglobin levels were significantly increased. RBV-treated patients showed an increase in aggregated band 3, which was associated with a significantly increased binding of autologous antibodies and complement C3 fragments indicating an erithrophagocytic removal by reticuloendothelial system. (HEPATOLOGY 2000;31:997-1004.)Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma worldwide. 1,2 A major therapeutic goal in HCV-infected patients is to achieve early eradication of the virus, and to prevent severe long-term clinical complications. Interferon alfa (IFN-␣) is currently the only therapy that has been shown to have beneficial effects in chronic hepatitis type C. However, with a standard regimen of 3 million U administered 3 times per week for 6 to 12 months, only a small fraction of approximately 15% to 20% of the patients showed a sustained response with normalization of serum alanine transferase levels and serum HCV-RNA clearance. 3 Ribavirin (1-␤-D-ribofuranosyl-1H-1, 2,4-triazole-3-carboxamide) (RBV) is a water soluble synthetic guanosine analog that exerts antiviral activity against DNA and RNA viruses after intracellular phosphorylation. 4 Current studies indicate that combination therapy with RBV and IFN is associated with higher rates of sustained virological, biochemical, and histological response compared to IFN monotherapy. [5][6][7][8][9][10] The major side effect of RBV treatment is the occurrence of a reversible hemolytic anemia in a substantial proportion of treated patients. 11 The underlying mechanism is unknown. Studies on steady-state pharmacokinetics of RBV have shown that erythrocyte concentration of RBV greatly exceeds plasma concentrations 12 and that RBV is a transported permeant for the (es) nucleoside transporter in human erythrocytes...

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“…Antiviral chemotherapy for influenza has been investigated and only ribavirin and amantadine have been used in clinical practice as anti-influenza drugs (Davies et al, 1964;Prusinger et sl., 1973), but the uses of ribavirin were restricted to severely infected patients because of concerns about toxicity (McLung et al, 1983;Canonico et al, 1984). Amantadine has been used for influenzaA infection but is not effective against influenza B infection ( Smorodintsev et al, 1970;Hayden et al, 1981).…”

Section: Discussionmentioning

confidence: 99%

Establishment of the Haemadsorption-Based Colorimetric Assay for the Screening of Anti-Influenza Compounds

Takeuchi

Baba

Shigeta

1993

Antivir Chem Chemother

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SummaryWe established a haemadsorption-based colorimetric assay system, which may be used to screen a large number of anti-influenza compounds. Madin Darby canine kidney (MDCK) cells infected with influenza virus were cultured in the presenct"~ftestcompounds and after 3 days of infection gUin'e~pig erythrocytes .(GPE) were added to infected MDCK cells. After 4 washings of the cells the adsorbed GPE were lysed with distilled water, and peroxidase activities contained in GPE were measured using o-phenylendiamine and H 2 0 2 as substrates. The peroxidase activity that was read as optical density of oxidized o-phenylendiamine (quinoid form) correlated well with the dose of virus and day of infection in MDCK cells. Fifty per cent inhibitory concentration (ICso) of 1-(f3-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (ribavirin) and adamantanamine hydrochloride (amantadine) against influenza virus A1H3N2Ilshikawa and influenza B/Singapore, the ICsosof ribavirin to influenza A and B were O.5J.Lg mr " to 1.0J.Lg mr ' respectively. On the other hand, the IC so of amantadine for influenza A was 1 J.Lg ml" but was more than 100 J.Lg mr" for influenza B virus. By this method, ribavirin, 5-ethynyl-1-f3-Dribofuranosylimidazole-4-carboxamide (EICAR), 3-(f3-D-ribofuranosyl)-4-hydroxypyrazole-5-carboxamide (pyrazofurin) have shown inhibitory effects for virus replication at lower concentrations than their cytotoxic doses. On the other hand carbocyclic citidine (carbodine) was cytotoxic at the concentration of virus inhibition. Ribavirin and pyrazofurin showed one tenth or less EC so for influenza A and B viruses by the haemadsorption-based colorimetric assay compared with the EC so by TCID so method. It is possible to estimate the inhibitory effect of antiviral compounds

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Hematological and bone marrow effects of ribavirin in rhesus monkeys

Cited by 46 publications

References 10 publications

Ribavirin prophylaxis and therapy for experimental argentine hemorrhagic fever

Ribavirin prophylaxis and therapy for experimental argentine hemorrhagic fever

Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: Role of membrane oxidative damage

Establishment of the Haemadsorption-Based Colorimetric Assay for the Screening of Anti-Influenza Compounds

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