ribavirin

Ribavirin is primarily used to treat chronic hepatitis C and viral hemorrhagic fevers (an orphan indication in most countries).{{cite web|title=Rebetol, Ribasphere (ribavirin) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=23 February 2014 |url= http://reference.medscape.com/drug/rebetol-ribasphere-ribavirin-342625#showall|url-status=live|archive-url=https://web.archive.org/web/20140228132755/http://reference.medscape.com/drug/rebetol-ribasphere-ribavirin-342625#showall|archive-date=28 February 2014}} Its efficacy for these purposes has been questioned in light of its Food and Drug Administration boxed warning against its use as monotherapy for chronic hepatitis C. Thus, it may be prescribed in the United States only as an adjunct to one or more other medications. Its efficacy against viruses other than HCV, including those that cause viral hemorrhagic fever, has not been conclusively demonstrated. In effect, it is not approved in the United States for treatment of viruses other than HCV.{{Cite web |date=2023-03-27 |title=Copegus: Package Insert |url=https://www.drugs.com/pro/copegus.html |access-date=2024-01-19 |website=Drugs.com |language=en}}{{Cite book | vauthors = Safrin S |title=Katzung's Basic & Clinical Pharmacology |publisher=McGraw Hill |year=2024 |edition=16th |at=Other antiviral agents: Ribavirin |chapter=Chapter 49: Antiviral Agents}}

For chronic HCV infection, the oral (capsule or tablet) form of ribavirin is used only in combination with pegylated interferon alfa.{{cite journal | vauthors = Paeshuyse J, Dallmeier K, Neyts J | title = Ribavirin for the treatment of chronic hepatitis C virus infection: a review of the proposed mechanisms of action | journal = Current Opinion in Virology | volume = 1 | issue = 6 | pages = 590–598 | date = December 2011 | pmid = 22440916 | doi = 10.1016/j.coviro.2011.10.030 }}{{cite journal | vauthors = Flori N, Funakoshi N, Duny Y, Valats JC, Bismuth M, Christophorou D, Daurès JP, Blanc P | title = Pegylated interferon-α2a and ribavirin versus pegylated interferon-α2b and ribavirin in chronic hepatitis C : a meta-analysis | journal = Drugs | volume = 73 | issue = 3 | pages = 263–277 | date = March 2013 | pmid = 23436591 | doi = 10.1007/s40265-013-0027-1 | s2cid = 46334977 }}{{cite journal | vauthors = Druyts E, Thorlund K, Wu P, Kanters S, Yaya S, Cooper CL, Mills EJ | title = Efficacy and safety of pegylated interferon alfa-2a or alfa-2b plus ribavirin for the treatment of chronic hepatitis C in children and adolescents: a systematic review and meta-analysis | journal = Clinical Infectious Diseases | volume = 56 | issue = 7 | pages = 961–967 | date = April 2013 | pmid = 23243171 | doi = 10.1093/cid/cis1031 | doi-access = free }}{{cite journal | vauthors = Zeuzem S, Poordad F | title = Pegylated-interferon plus ribavirin therapy in the treatment of CHC: individualization of treatment duration according to on-treatment virologic response | journal = Current Medical Research and Opinion | volume = 26 | issue = 7 | pages = 1733–1743 | date = July 2010 | pmid = 20482242 | doi = 10.1185/03007995.2010.487038 | s2cid = 206965239 }} Statins may improve this combination's efficacy in treating hepatitis C.{{cite journal | vauthors = Zhu Q, Li N, Han Q, Zhang P, Yang C, Zeng X, Chen Y, Lv Y, Liu X, Liu Z | title = Statin therapy improves response to interferon alfa and ribavirin in chronic hepatitis C: a systematic review and meta-analysis | journal = Antiviral Research | volume = 98 | issue = 3 | pages = 373–379 | date = June 2013 | pmid = 23603497 | doi = 10.1016/j.antiviral.2013.04.009 }} When possible, genotyping of the specific viral strain is done; and ribavirin is only used as a dose-escalating{{Efn-la|Begins with a low dose, at or near the lowest point of the expected therapeutic index, and then the dose is progressively increased until achieving desired effects.|name=a|group=}} adjuvant to specific combinations of genotypes and other medications.{{cite journal | vauthors = Chung RT, Ghany MG, Kim AY, Marks KM, Naggie S, Vargas HE, Aronsohn AI, Bhattacharya D, Broder T, Falade-Nwulia OO, Fontana RJ, Gordon SC, Heller T, Holmberg SD, Jhaveri R, Jonas MM, Kiser JJ, Linas BP, Lo Re V, Morgan TR, Nahass RG, Peters MG, Reddy KR, Reynolds A, Scott JD, Searson G, Swan T, Terrault NA, Trooskin SB, Wong JB | collaboration = AASLD-IDSA HCV Guidance Panel | title = Hepatitis C Guidance 2018 Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection | journal = Clinical Infectious Diseases | volume = 67 | issue = 10 | pages = 1477–1492 | date = October 2018 | pmid = 30215672 | pmc = 7190892 | doi = 10.1093/cid/ciy585 }}

Acute hepatitis C infection (within the first 6 months) often does not require immediate treatment, as many infections eventually resolve without treatment.{{cite journal | title = EASL Recommendations on Treatment of Hepatitis C 2018 | journal = Journal of Hepatology | volume = 69 | issue = 2 | pages = 461–511 | date = August 2018 | pmid = 29650333 | doi = 10.1016/j.jhep.2018.03.026 | vauthors = Pawlotsky J, Negro F, Aghemo A, Berenguer M, Dalgard O, Dusheiko G, Marra F, Puoti M, Wedemeyer H }} When the decision is made to treat acute hepatitis C, ribavirin may be used as an adjunct to several drug combinations. However, other medications are still preferred.

Ribavirin is the only known treatment for a variety of viral hemorrhagic fevers, including Lassa fever, Crimean-Congo hemorrhagic fever, Venezuelan hemorrhagic fever, and Hantavirus infection, although data regarding these infections are scarce and the drug might be effective only in early stages.{{cite book|url=http://www.rki.de/cln_091/nn_468470/DE/Content/InfAZ/Steckbriefe/Steckbriefe__120606,templateId=raw,property=publicationFile.pdf/Steckbriefe_120606.pdf|title=Steckbriefe seltener und importierter Infektionskrankheiten|trans-title=Characteristics of rare and imported infectious diseases|publisher=Robert Koch Institute|isbn=978-3-89606-095-2|location=Berlin|year=2006|url-status=dead|archive-url=https://web.archive.org/web/20110929151854/http://www.rki.de/cln_091/nn_468470/DE/Content/InfAZ/Steckbriefe/Steckbriefe__120606%2CtemplateId%3Draw%2Cproperty%3DpublicationFile.pdf/Steckbriefe_120606.pdf|archive-date=2011-09-29}}{{cite journal | vauthors = Ascioglu S, Leblebicioglu H, Vahaboglu H, Chan KA | title = Ribavirin for patients with Crimean-Congo haemorrhagic fever: a systematic review and meta-analysis | journal = The Journal of Antimicrobial Chemotherapy | volume = 66 | issue = 6 | pages = 1215–1222 | date = June 2011 | pmid = 21482564 | doi = 10.1093/jac/dkr136 | doi-access = free }}{{cite journal | vauthors = Bausch DG, Hadi CM, Khan SH, Lertora JJ | title = Review of the literature and proposed guidelines for the use of oral ribavirin as postexposure prophylaxis for Lassa fever | journal = Clinical Infectious Diseases | volume = 51 | issue = 12 | pages = 1435–1441 | date = December 2010 | pmid = 21058912 | pmc = 7107935 | doi = 10.1086/657315 }}{{cite journal | vauthors = Soares-Weiser K, Thomas S, Thomson G, Garner P | title = Ribavirin for Crimean-Congo hemorrhagic fever: systematic review and meta-analysis | journal = BMC Infectious Diseases | volume = 10 | pages = 207 | date = July 2010 | pmid = 20626907 | pmc = 2912908 | doi = 10.1186/1471-2334-10-207 | doi-access = free }} It is noted by the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) that "Ribavirin has poor in vitro and in vivo activity against the filoviruses (Ebola{{cite journal | vauthors = Goeijenbier M, van Kampen JJ, Reusken CB, Koopmans MP, van Gorp EC | title = Ebola virus disease: a review on epidemiology, symptoms, treatment and pathogenesis | journal = The Netherlands Journal of Medicine | volume = 72 | issue = 9 | pages = 442–448 | date = November 2014 | pmid = 25387613 | url = http://www.njmonline.nl/getpdf.php?t=a&id=10001148 | url-status = live | archive-url = https://web.archive.org/web/20141129144852/http://www.njmonline.nl/getpdf.php?t=a&id=10001148 | archive-date = 2014-11-29 }} and Marburg) and the flaviviruses (dengue, yellow fever, Omsk hemorrhagic fever, and Kyasanur forest disease)"{{Cite book|title = Medical Management of Biological Casualties Handbook|publisher = United States Government Printing Office|year = 2011|isbn = 978-0-16-090015-0|pages = 115}} The aerosol form has been used in the past to treat respiratory syncytial virus-related diseases in children, although the evidence to support this is rather weak.{{cite journal | vauthors = Ventre K, Randolph AG | title = Ribavirin for respiratory syncytial virus infection of the lower respiratory tract in infants and young children | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD000181 | date = January 2007 | pmid = 17253446 | doi = 10.1002/14651858.CD000181.pub3 | veditors = Ventre K }}

Despite questions surrounding its efficacy, ribavirin remains the only antiviral known to be effective in treating Lassa fever.{{Cite web |date=2023-09-26 |title=Treatment {{!}} Lassa Fever {{!}} CDC |url=https://www.cdc.gov/vhf/lassa/treatment/index.html |access-date=2024-01-20 |archive-url=https://web.archive.org/web/20230926004520/https://www.cdc.gov/vhf/lassa/treatment/index.html |archive-date=2023-09-26 }}

It has been used (in combination with ketamine, midazolam, and amantadine) in treatment of rabies.{{cite journal | vauthors = Hemachudha T, Ugolini G, Wacharapluesadee S, Sungkarat W, Shuangshoti S, Laothamatas J | title = Human rabies: neuropathogenesis, diagnosis, and management | journal = The Lancet. Neurology | volume = 12 | issue = 5 | pages = 498–513 | date = May 2013 | pmid = 23602163 | doi = 10.1016/S1474-4422(13)70038-3 | s2cid = 1798889 }}

Experimental data indicate that ribavirin may have useful activity against canine distemper and poxviruses.{{cite journal | vauthors = Elia G, Belloli C, Cirone F, Lucente MS, Caruso M, Martella V, Decaro N, Buonavoglia C, Ormas P | title = In vitro efficacy of ribavirin against canine distemper virus | journal = Antiviral Research | volume = 77 | issue = 2 | pages = 108–113 | date = February 2008 | pmid = 17949825 | doi = 10.1016/j.antiviral.2007.09.004 }}{{cite journal | vauthors = Baker RO, Bray M, Huggins JW | title = Potential antiviral therapeutics for smallpox, monkeypox and other orthopoxvirus infections | journal = Antiviral Research | volume = 57 | issue = 1–2 | pages = 13–23 | date = January 2003 | pmid = 12615299 | pmc = 9533837 | doi = 10.1016/S0166-3542(02)00196-1 }} Ribavirin has also been used as a treatment for herpes simplex virus. One small study found that ribavirin treatment reduced the severity of herpes outbreaks and promoted recovery, as compared with placebo treatment.{{cite journal | vauthors = Bierman SM, Kirkpatrick W, Fernandez H | title = Clinical efficacy of ribavirin in the treatment of genital herpes simplex virus infection | journal = Chemotherapy | volume = 27 | issue = 2 | pages = 139–145 | year = 1981 | pmid = 7009087 | doi = 10.1159/000237969 }} Another study found that ribavirin potentiated the antiviral effect of acyclovir.{{cite journal | vauthors = Pancheva SN | title = Potentiating effect of ribavirin on the anti-herpes activity of acyclovir | journal = Antiviral Research | volume = 16 | issue = 2 | pages = 151–161 | date = September 1991 | pmid = 1665959 | doi = 10.1016/0166-3542(91)90021-I }}

Some interest has been seen in its possible use as a treatment for cancers with elevated eukaryotic translation initiation factor eIF4E, especially acute myeloid leukemia (AML) as well as in head and neck cancers.{{cite journal | vauthors = Kast RE | title = Ribavirin in cancer immunotherapies: controlling nitric oxide helps generate cytotoxic lymphocyte | journal = Cancer Biology & Therapy | volume = 1 | issue = 6 | pages = 626–630 | date = November–December 2002 | pmid = 12642684 | doi = 10.4161/cbt.310 | s2cid = 24010404 | doi-access = free }}{{cite journal | vauthors = Borden KL, Culjkovic-Kraljacic B | title = Ribavirin as an anti-cancer therapy: acute myeloid leukemia and beyond? | journal = Leukemia & Lymphoma | volume = 51 | issue = 10 | pages = 1805–1815 | date = October 2010 | pmid = 20629523 | pmc = 2950216 | doi = 10.3109/10428194.2010.496506 }}{{cite journal | vauthors = Dunn LA, Fury MG, Sherman EJ, Ho AA, Katabi N, Haque SS, Pfister DG | title = Phase I study of induction chemotherapy with afatinib, ribavirin, and weekly carboplatin and paclitaxel for stage IVA/IVB human papillomavirus-associated oropharyngeal squamous cell cancer | journal = Head & Neck | volume = 40 | issue = 2 | pages = 233–241 | date = February 2018 | pmid = 28963790 | pmc = 6760238 | doi = 10.1002/hed.24938 }}{{cite journal | vauthors = Burman B, Drutman SB, Fury MG, Wong RJ, Katabi N, Ho AL, Pfister DG | title = Pharmacodynamic and therapeutic pilot studies of single-agent ribavirin in patients with human papillomavirus-related malignancies | journal = Oral Oncology | volume = 128 | pages = 105806 | date = May 2022 | pmid = 35339025 | pmc = 9788648 | doi = 10.1016/j.oraloncology.2022.105806 }} Ribavirin targeted eIF4E in AML patients in monotherapy and combination studies and this corresponded to objective clinical responses including complete remissions.{{cite journal | vauthors = Assouline S, Culjkovic B, Cocolakis E, Rousseau C, Beslu N, Amri A, Caplan S, Leber B, Roy DC, Miller WH, Borden KL | title = Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin | journal = Blood | volume = 114 | issue = 2 | pages = 257–260 | date = July 2009 | pmid = 19433856 | doi = 10.1182/blood-2009-02-205153 | s2cid = 28957125 | doi-access = free }} Ribavirin resistance in AML patients arose leading to loss of eIF4E targeting and relapse. Resistance was caused by deactivation of ribavirin through its glucuronidation in AML cells or impaired drug entry/retention in the AML cells. There may be additional forms of ribavirin resistance displayed by cancer cells. In HPV related oropharyngeal cancers, ribavirin reduced levels of phosphorylated form of eIF4E in some patients. The best response here was stable disease but another head and neck study had more promising results.

{{Main list|List of adverse effects of ribavirin}}

The medication has two FDA "black box" warnings: One raises concerns that use before or during pregnancy by either sex may result in birth defects in the baby, and the other is regarding the risk of red blood cell breakdown.{{cite web|title=Copedgus|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021511s023lbl.pdf|website=FDA.gov|access-date=16 April 2017|url-status=live|archive-url=https://web.archive.org/web/20141103185016/http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021511s023lbl.pdf|archive-date=3 November 2014}}

Ribavirin should not be given with zidovudine because of the increased risk of anemia;{{cite journal | vauthors = Alvarez D, Dieterich DT, Brau N, Moorehead L, Ball L, Sulkowski MS | title = Zidovudine use but not weight-based ribavirin dosing impacts anaemia during HCV treatment in HIV-infected persons | journal = Journal of Viral Hepatitis | volume = 13 | issue = 10 | pages = 683–689 | date = October 2006 | pmid = 16970600 | doi = 10.1111/j.1365-2893.2006.00749.x | s2cid = 21474337 }} concurrent use with didanosine should likewise be avoided because of an increased risk of mitochondrial toxicity.{{cite journal | vauthors = Bani-Sadr F, Carrat F, Pol S, Hor R, Rosenthal E, Goujard C, Morand P, Lunel-Fabiani F, Salmon-Ceron D, Piroth L, Pialoux G, Bentata M, Cacoub P, Perronne C | title = Risk factors for symptomatic mitochondrial toxicity in HIV/hepatitis C virus-coinfected patients during interferon plus ribavirin-based therapy | journal = Journal of Acquired Immune Deficiency Syndromes | volume = 40 | issue = 1 | pages = 47–52 | date = September 2005 | pmid = 16123681 | doi = 10.1097/01.qai.0000174649.51084.46 | s2cid = 9364536 | collaboration = Anrs Hc02-Ribavic Study Team | doi-access = free }}

It is a guanosine (ribonucleic) analog used to stop viral RNA synthesis and viral mRNA capping, thus, it is a nucleoside analog. Ribavirin is a prodrug, which when metabolized resembles purine RNA nucleotides. In this form, it interferes with RNA metabolism required for viral replication. Over five direct and indirect mechanisms have been proposed for its mechanism of action.{{cite journal | vauthors = Graci JD, Cameron CE | title = Mechanisms of action of ribavirin against distinct viruses | journal = Reviews in Medical Virology | volume = 16 | issue = 1 | pages = 37–48 | date = January 2006 | pmid = 16287208 | pmc = 7169142 | doi = 10.1002/rmv.483 }} The enzyme inosine triphosphate pyrophosphatase (ITPase) dephosphorylates ribavirin triphosphate in vitro to ribavirin monophosphate, and ITPase reduced enzymatic activity present in 30% of humans potentiates mutagenesis in hepatitis C virus.{{cite journal | vauthors = Nyström K, Wanrooij PH, Waldenström J, Adamek L, Brunet S, Said J, Nilsson S, Wind-Rotolo M, Hellstrand K, Norder H, Tang KW, Lagging M | title = Inosine Triphosphate Pyrophosphatase Dephosphorylates Ribavirin Triphosphate and Reduced Enzymatic Activity Potentiates Mutagenesis in Hepatitis C Virus | journal = Journal of Virology | volume = 92 | issue = 19 | pages = 01087–18 | date = October 2018 | pmid = 30045981 | pmc = 6146798 | doi = 10.1128/JVI.01087-18 | doi-access = free }}

Ribavirin's amide group can make the native nucleoside drug resemble adenosine or guanosine, depending on its rotation. For this reason, when ribavirin is incorporated into RNA, as a base analog of either adenine or guanine, it pairs equally well with either uracil or cytosine, inducing mutations in RNA-dependent replication in RNA viruses. Such hypermutation can be lethal to RNA viruses.{{cite journal | vauthors = Ortega-Prieto AM, Sheldon J, Grande-Pérez A, Tejero H, Gregori J, Quer J, Esteban JI, Domingo E, Perales C | title = Extinction of hepatitis C virus by ribavirin in hepatoma cells involves lethal mutagenesis | journal = PLOS ONE | volume = 8 | issue = 8 | pages = e71039 | year = 2013 | pmid = 23976977 | pmc = 3745404 | doi = 10.1371/journal.pone.0071039 | veditors = Vartanian JP | doi-access = free | bibcode = 2013PLoSO...871039O }}{{cite journal | vauthors = Crotty S, Cameron C, Andino R | title = Ribavirin's antiviral mechanism of action: lethal mutagenesis? | journal = Journal of Molecular Medicine | volume = 80 | issue = 2 | pages = 86–95 | date = February 2002 | pmid = 11907645 | doi = 10.1007/s00109-001-0308-0 | s2cid = 52851826 }}

Neither of these mechanisms explains ribavirin's effect on many DNA viruses, which is more of a mystery, especially given the complete inactivity of ribavirin's 2' deoxyribose analogue, which suggests that the drug functions only as an RNA nucleoside mimic, and never a DNA nucleoside mimic. Ribavirin 5'-monophosphate inhibits cellular inosine monophosphate dehydrogenase, thereby depleting intracellular pools of GTP.{{cite journal | vauthors = Leyssen P, De Clercq E, Neyts J | title = The anti-yellow fever virus activity of ribavirin is independent of error-prone replication | journal = Molecular Pharmacology | volume = 69 | issue = 4 | pages = 1461–1467 | date = April 2006 | pmid = 16421290 | doi = 10.1124/mol.105.020057 | s2cid = 8158590 }}{{failed verification|date=April 2022|reason=The cited paper refers only to an RNA virus and so does not support this section's assertion. A reference to a DNA virus is needed here.}}

{{More medical citations needed|eIF4E targeting in cancer|date=April 2023}}

The eukaryotic translation initiation factor eIF4E plays multiple roles in RNA metabolism with translation being the best described. Biophysical and NMR studies first revealed that ribavirin directly bound the eIF4E, providing another mechanism for its action.{{cite journal | vauthors = Kentsis A, Topisirovic I, Culjkovic B, Shao L, Borden KL | title = Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 52 | pages = 18105–18110 | date = December 2004 | pmid = 15601771 | pmc = 539790 | doi = 10.1073/pnas.0406927102 | bibcode = 2004PNAS..10118105K | doi-access = free }}{{cite journal | vauthors = Kentsis A, Volpon L, Topisirovic I, Soll CE, Culjkovic B, Shao L, Borden KL | title = Further evidence that ribavirin interacts with eIF4E | journal = RNA | volume = 11 | issue = 12 | pages = 1762–1766 | date = December 2005 | pmid = 16251386 | pmc = 1370864 | doi = 10.1261/rna.2238705 }}{{cite journal | vauthors = Volpon L, Osborne MJ, Zahreddine H, Romeo AA, Borden KL | title = Conformational changes induced in the eukaryotic translation initiation factor eIF4E by a clinically relevant inhibitor, ribavirin triphosphate | journal = Biochemical and Biophysical Research Communications | volume = 434 | issue = 3 | pages = 614–619 | date = May 2013 | pmid = 23583375 | pmc = 3659399 | doi = 10.1016/j.bbrc.2013.03.125 }} ³H Ribavirin also interacts with eIF4E in cells. While inosine monophosphate dehydrogenase (IMPDH) presumably only binds the ribavirin monophosphate metabolite (RMP), eIF4E can bind ribavirin and with higher affinity ribavirin's phosphorylated forms. In many cell lines, studies into steady state levels of metabolites indicate that ribavirin triphosphate (RTP) is more abundant than the RMP metabolite which is the IMPDH ligand.{{cite journal | vauthors = Smee DF, Matthews TR | title = Metabolism of ribavirin in respiratory syncytial virus-infected and uninfected cells | journal = Antimicrobial Agents and Chemotherapy | volume = 30 | issue = 1 | pages = 117–121 | date = July 1986 | pmid = 3752974 | pmc = 176447 | doi = 10.1128/AAC.30.1.117 }}{{cite journal | vauthors = Page T, Connor JD | title = The metabolism of ribavirin in erythrocytes and nucleated cells | journal = The International Journal of Biochemistry | volume = 22 | issue = 4 | pages = 379–383 | date = January 1990 | pmid = 2159925 | doi = 10.1016/0020-711X(90)90140-X }} RTP binds to eIF4E in its cap-binding site as observed by NMR. Ribavirin inhibits eIF4E activities in cells including in its RNA export, translation and oncogenic activities lines.{{cite journal | vauthors = Pettersson F, Yau C, Dobocan MC, Culjkovic-Kraljacic B, Retrouvey H, Puckett R, Flores LM, Krop IE, Rousseau C, Cocolakis E, Borden KL, Benz CC, Miller WH | title = Ribavirin treatment effects on breast cancers overexpressing eIF4E, a biomarker with prognostic specificity for luminal B-type breast cancer | journal = Clinical Cancer Research | volume = 17 | issue = 9 | pages = 2874–2884 | date = May 2011 | pmid = 21415224 | pmc = 3086959 | doi = 10.1158/1078-0432.CCR-10-2334 }}{{cite journal | vauthors = Bollmann F, Fechir K, Nowag S, Koch K, Art J, Kleinert H, Pautz A | title = Human inducible nitric oxide synthase (iNOS) expression depends on chromosome region maintenance 1 (CRM1)- and eukaryotic translation initiation factor 4E (elF4E)-mediated nucleocytoplasmic mRNA transport | journal = Nitric Oxide | volume = 30 | pages = 49–59 | date = April 2013 | pmid = 23471078 | doi = 10.1016/j.niox.2013.02.083 }}{{cite journal | vauthors = Shi F, Len Y, Gong Y, Shi R, Yang X, Naren D, Yan T | title = Ribavirin Inhibits the Activity of mTOR/eIF4E, ERK/Mnk1/eIF4E Signaling Pathway and Synergizes with Tyrosine Kinase Inhibitor Imatinib to Impair Bcr-Abl Mediated Proliferation and Apoptosis in Ph+ Leukemia | journal = PLOS ONE | volume = 10 | issue = 8 | pages = e0136746 | date = 2015-08-28 | pmid = 26317515 | pmc = 4552648 | doi = 10.1371/journal.pone.0136746 | bibcode = 2015PLoSO..1036746S | veditors = Eaves CJ | doi-access = free }}{{cite journal | vauthors = Zismanov V, Attar-Schneider O, Lishner M, Heffez Aizenfeld R, Tartakover Matalon S, Drucker L | title = Multiple myeloma proteostasis can be targeted via translation initiation factor eIF4E | journal = International Journal of Oncology | volume = 46 | issue = 2 | pages = 860–870 | date = February 2015 | pmid = 25422161 | doi = 10.3892/ijo.2014.2774 | doi-access = free }}{{cite journal | vauthors = Dai D, Chen H, Tang J, Tang Y | title = Inhibition of mTOR/eIF4E by anti-viral drug ribavirin effectively enhances the effects of paclitaxel in oral tongue squamous cell carcinoma | journal = Biochemical and Biophysical Research Communications | volume = 482 | issue = 4 | pages = 1259–1264 | date = January 2017 | pmid = 27932243 | doi = 10.1016/j.bbrc.2016.12.025 }}{{cite journal | vauthors = Volpin F, Casaos J, Sesen J, Mangraviti A, Choi J, Gorelick N, Frikeche J, Lott T, Felder R, Scotland SJ, Eisinger-Mathason TS, Brem H, Tyler B, Skuli N | title = Use of an anti-viral drug, Ribavirin, as an anti-glioblastoma therapeutic | journal = Oncogene | volume = 36 | issue = 21 | pages = 3037–3047 | date = May 2017 | pmid = 27941882 | doi = 10.1038/onc.2016.457 | s2cid = 21655102 }}{{cite journal | vauthors = Wang G, Li Z, Li Z, Huang Y, Mao X, Xu C, Cui S | title = Targeting eIF4E inhibits growth, survival and angiogenesis in retinoblastoma and enhances efficacy of chemotherapy | journal = Biomedicine & Pharmacotherapy | volume = 96 | pages = 750–756 | date = December 2017 | pmid = 29049978 | doi = 10.1016/j.biopha.2017.10.034 }}{{cite journal | vauthors = Xi C, Wang L, Yu J, Ye H, Cao L, Gong Z | title = Inhibition of eukaryotic translation initiation factor 4E is effective against chemo-resistance in colon and cervical cancer | journal = Biochemical and Biophysical Research Communications | volume = 503 | issue = 4 | pages = 2286–2292 | date = September 2018 | pmid = 29959920 | doi = 10.1016/j.bbrc.2018.06.150 | s2cid = 49634908 }}{{cite journal | vauthors = Jin J, Xiang W, Wu S, Wang M, Xiao M, Deng A | title = Targeting eIF4E signaling with ribavirin as a sensitizing strategy for ovarian cancer | journal = Biochemical and Biophysical Research Communications | volume = 510 | issue = 4 | pages = 580–586 | date = March 2019 | pmid = 30739792 | doi = 10.1016/j.bbrc.2019.01.117 | s2cid = 73419809 }}{{cite journal | vauthors = Urtishak KA, Wang LS, Culjkovic-Kraljacic B, Davenport JW, Porazzi P, Vincent TL, Teachey DT, Tasian SK, Moore JS, Seif AE, Jin S, Barrett JS, Robinson BW, Chen IL, Harvey RC, Carroll MP, Carroll AJ, Heerema NA, Devidas M, Dreyer ZE, Hilden JM, Hunger SP, Willman CL, Borden KL, Felix CA | title = Targeting EIF4E signaling with ribavirin in infant acute lymphoblastic leukemia | journal = Oncogene | volume = 38 | issue = 13 | pages = 2241–2262 | date = March 2019 | pmid = 30478448 | pmc = 6440839 | doi = 10.1038/s41388-018-0567-7 }} In AML patients treated with ribavirin, ribavirin blocked the nuclear import of eIF4E through interfering with its interaction with its nuclear importer, Importin 8, thereby impairing its nuclear activities.{{cite journal | vauthors = Volpon L, Culjkovic-Kraljacic B, Osborne MJ, Ramteke A, Sun Q, Niesman A, Chook YM, Borden KL | title = Importin 8 mediates m7G cap-sensitive nuclear import of the eukaryotic translation initiation factor eIF4E | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 19 | pages = 5263–5268 | date = May 2016 | pmid = 27114554 | pmc = 4868427 | doi = 10.1073/pnas.1524291113 | bibcode = 2016PNAS..113.5263V | doi-access = free }}{{cite journal | vauthors = Assouline S, Gasiorek J, Bergeron J, Lambert C, Culjkovic-Kraljacic B, Cocolakis E, Zakaria C, Szlachtycz D, Yee K, Borden KL | title = Molecular targeting of the UDP-glucuronosyltransferase enzymes in high-eukaryotic translation initiation factor 4E refractory/relapsed acute myeloid leukemia patients: a randomized phase II trial of vismodegib, ribavirin with or without decitabine | journal = Haematologica | date = March 2023 | volume = 108 | issue = 11 | pages = 2946–2958 | pmid = 36951168 | doi = 10.3324/haematol.2023.282791 | pmc = 10620574 | s2cid = 257733013 | doi-access = free }}{{cite journal | vauthors = Assouline S, Culjkovic-Kraljacic B, Bergeron J, Caplan S, Cocolakis E, Lambert C, Lau CJ, Zahreddine HA, Miller WH, Borden KL | title = A phase I trial of ribavirin and low-dose cytarabine for the treatment of relapsed and refractory acute myeloid leukemia with elevated eIF4E | journal = Haematologica | volume = 100 | issue = 1 | pages = e7–e9 | date = January 2015 | pmid = 25425688 | pmc = 4281321 | doi = 10.3324/haematol.2014.111245 }}{{cite journal | vauthors = Zahreddine HA, Culjkovic-Kraljacic B, Assouline S, Gendron P, Romeo AA, Morris SJ, Cormack G, Jaquith JB, Cerchietti L, Cocolakis E, Amri A, Bergeron J, Leber B, Becker MW, Pei S, Jordan CT, Miller WH, Borden KL | title = The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation | journal = Nature | volume = 511 | issue = 7507 | pages = 90–93 | date = July 2014 | pmid = 24870236 | pmc = 4138053 | doi = 10.1038/nature13283 | bibcode = 2014Natur.511...90Z }} Clinical relapse in AML patients corresponded to loss of ribavirin binding leading to nuclear re-entry of eIF4E and re-emergence of its nuclear activities.

Ribavirin was first made in 1972 under the National Cancer Institute's Virus-Cancer program.{{cite journal | vauthors = Snell NJ | title = Ribavirin--current status of a broad spectrum antiviral agent | journal = Expert Opinion on Pharmacotherapy | volume = 2 | issue = 8 | pages = 1317–1324 | date = August 2001 | pmid = 11585000 | doi = 10.1517/14656566.2.8.1317 | s2cid = 46564870 }} This was done by researchers from International Chemical and Nuclear Corporation including Roberts A. Smith, Joseph T. Witkovski and Roland K. Robins.{{Cite web|title = Ribavirin History|url = http://www.news-medical.net/health/Ribavirin-History.aspx|website = News-Medical.net|date = 12 April 2010|access-date = 2016-02-19|url-status = live|archive-url = https://web.archive.org/web/20160302004242/http://www.news-medical.net/health/Ribavirin-History.aspx|archive-date = 2016-03-02}} It was reported that ribavirin was active against a variety of RNA and DNA viruses in culture and in animals, without undue toxicity in the context of cancer chemotherapies.{{cite journal | vauthors = Sidwell RW, Huffman JH, Khare GP, Allen LB, Witkowski JT, Robins RK | title = Broad-spectrum antiviral activity of Virazole: 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide | journal = Science | volume = 177 | issue = 4050 | pages = 705–706 | date = August 1972 | pmid = 4340949 | doi = 10.1126/science.177.4050.705 | s2cid = 43106875 | bibcode = 1972Sci...177..705S }} By the late 1970s, the Virus-Cancer program was widely considered a failure, and the drug development was abandoned.{{citation needed|date=November 2022}}

After the US Government announced that AIDS was caused by a retrovirus in 1984, drugs examined during the Virus-Cancer program and its focus on retroviruses were re-examined. Although the FDA first approved ribavirin as an antiviral in 1986, it was not indicated to treat HIV or AIDS. As a result, many people with AIDS sought to obtain black market ribavirin via buyer's clubs. The drug was approved for investigational use against hantavirus in the United States in 1993, but the results from a non-randomized uncontrolled trial were not encouraging: 71% of recipients became anemic and 47% died.

In 2002 with the SARS outbreak, early speculation focused on ribavirin as a possible anti-SARS agent.{{cite journal | vauthors = Koren G, King S, Knowles S, Phillips E | title = Ribavirin in the treatment of SARS: A new trick for an old drug? | journal = CMAJ | volume = 168 | issue = 10 | pages = 1289–1292 | date = May 2003 | pmid = 12743076 | pmc = 154189 }} Early protocols adopted in Hong Kong adopted a "Hit Hard Hit Early" approach treating SARS with high doses of off-label steroids and Ribavirin.{{cite journal | vauthors = Leung CW, Kwan YW, Ko PW, Chiu SS, Loung PY, Fong NC, Lee LP, Hui YW, Law HK, Wong WH, Chan KH, Peiris JS, Lim WW, Lau YL, Chiu MC | title = Severe acute respiratory syndrome among children | journal = Pediatrics | volume = 113 | issue = 6 | pages = e535–e543 | date = June 2004 | pmid = 15173534 | doi = 10.1542/peds.113.6.e535 }} Unfortunately, it later turned out this haphazard approach was at best ineffective and at worst fatal, with many deaths attributed to SARS caused by ribavirin toxicity.{{cite journal | vauthors = Crowe D |title=SARS - Sterioid and Ribavirin Scandal |date=February 2020 |doi=10.13140/RG.2.2.25308.74881 |url=https://www.researchgate.net/publication/339484995 | via = researchgate.net | journal = Unpublished Preprint | quote = Author died before publication}}{{unreliable source|date=June 2024|reason=Not peer reviewed}}

Ribavirin is the INN and USAN, whereas tribavirin is the BAN. Brand names of generic forms include Copegus, Ribasphere, Rebetol.

Ribavirin is possibly best viewed as a ribosyl purine analogue with an incomplete purine 6-membered ring. This structural resemblance historically prompted replacement of the 2' nitrogen of the triazole with a carbon (which becomes the 5' carbon in an imidazole), in an attempt to partly "fill out" the second ring--- but to no great effect. Such 5' imidazole riboside derivatives show antiviral activity with 5' hydrogen or halide, but the larger the substituent, the smaller the activity, and all proved less active than ribavirin.{{cite book | veditors=Smith RA, Kirkpatrick W | year=1980 | chapter=Ribavirin: structure and antiviral activity relationships | title=Ribavirin: A Broad Spectrum Antiviral Agent | pages=1–21 | publisher=Academic Press | location=New York }} Note that two natural products were already known with this imidazole riboside structure: substitution at the 5' carbon with OH results in pyrazofurin, an antibiotic with antiviral properties but unacceptable toxicity, and replacement with an amino group results in the natural purine synthetic precursor 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), which has only modest antiviral properties.{{citation needed|date=November 2022}}

{{main|Taribavirin}}

The most successful ribavirin derivative to date is the 3-carboxamidine derivative of the parent 3-carboxamide, first reported in 1973 by J. T. Witkowski et al.,{{cite journal | vauthors = Witkowski JT, Robins RK, Khare GP, Sidwell RW | title = Synthesis and antiviral activity of 1,2,4-triazole-3-thiocarboxamide and 1,2,4-triazole-3-carboxamidine ribonucleosides | journal = Journal of Medicinal Chemistry | volume = 16 | issue = 8 | pages = 935–937 | date = August 1973 | pmid = 4355593 | doi = 10.1021/jm00266a014 }} and now called taribavirin (former names "viramidine" and "ribamidine"). This drug shows a similar spectrum of antiviral activity to ribavirin, which is not surprising as it is now known to be a pro-drug for ribavirin. Taribavirin, however, has useful properties of less erythrocyte-trapping and better liver-targeting than ribavirin. The first property is due to taribavirin's basic amidine group which inhibits drug entry into RBCs, and the second property is probably due to increased concentration of the enzymes which convert amidine to amide in liver tissue.{{cite journal | vauthors = Sidwell RW, Bailey KW, Wong MH, Barnard DL, Smee DF | title = In vitro and in vivo influenza virus-inhibitory effects of viramidine | journal = Antiviral Research | volume = 68 | issue = 1 | pages = 10–17 | date = October 2005 | pmid = 16087250 | doi = 10.1016/j.antiviral.2005.06.003 }} Taribavirin completed phase III human trials in 2012.{{cite report |author=U.S. National Library of Medicine |date=2012-06-22 |title=Study of Viramidine to Ribavirin in Patients With Chronic Hepatitis C Who Are Treatment Naive (VISER2) |url=https://clinicaltrials.gov/ct2/show/NCT00093093 |publisher=National Institutes of Health |access-date=2021-03-25}}

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• {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/ribavirin | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Ribavirin }}

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