Ribavirin
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| Systematic (IUPAC) name |
| 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1H-1,2,4-triazole-3-carboxamide |
| Clinical data |
| Trade names |
Copegus, Rebetol, Virazole |
| AHFS/Drugs.com |
monograph |
| MedlinePlus |
a605018 |
| Pregnancy cat. |
X (AU) X (US) |
| Legal status |
Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US) |
| Routes |
Oral, inhalation |
| Pharmacokinetic data |
| Bioavailability |
64%[1] |
| Protein binding |
0%[1] |
| Metabolism |
Hepatic and intracellularly[1] |
| Half-life |
298 hours (multiple dose); 43.6 hours (single dose)[1] |
| Excretion |
Urine (61%), faeces (12%)[1] |
| Identifiers |
| CAS number |
36791-04-5 Y |
| ATC code |
J05AB04 |
| PubChem |
CID 37542 |
| DrugBank |
DB00811 |
| ChemSpider |
34439 Y |
| UNII |
49717AWG6K Y |
| KEGG |
D00423 Y |
| ChEMBL |
CHEMBL1643 Y |
| NIAID ChemDB |
000053 |
| Synonyms |
1-(β-D-Ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide |
| PDB ligand ID |
RBV (PDBe, RCSB PDB) |
| Chemical data |
| Formula |
C8H12N4O5 |
| Mol. mass |
244.206 |
SMILES
- OC[C@@H](O1)[C@@H](O)[C@@H](O)[C@@H]1N2N=C(C(N)=O)N=C2
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InChI
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InChI=1S/C8H12N4O5/c9-6(16)7-10-2-12(11-7)8-5(15)4(14)3(1-13)17-8/h2-5,8,13-15H,1H2,(H2,9,16)/t3-,4-,5-,8-/m1/s1 Y
Key:IWUCXVSUMQZMFG-AFCXAGJDSA-N Y
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| Y (what is this?) (verify) |
Ribavirin is a guanosine (ribonucleic) analog used to stop viral RNA synthesis and viral mRNA capping, thus, it is a nucleoside inhibitor.[2] Its brand names include Copegus, Rebetol, Ribasphere, Vilona, and Virazole, and it is an anti-viral drug used off-label for severe RSV infection (individually), (notably for persistent[2]) hepatitis C infection (can be used in conjunction with peginterferon alfa-2b or peginterferon alfa-2a), and some other viral infections. Ribavirin is a prodrug, which when metabolized resembles purine RNA nucleotides. In this form it interferes with RNA metabolism required for viral replication. How it exactly affects viral replication is unknown; many mechanisms have been proposed for this but none of these has been proven to date. Multiple mechanisms may be responsible for its actions.
It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[3]
Contents
- 1 Medical uses
- 2 Adverse effects
- 3 Mechanisms of action
- 3.1 RNA viruses
- 3.2 DNA viruses
- 4 History
- 5 Derivatives
- 5.1 Taribavirin (viramidine)
- 6 See also
- 7 References
- 8 External links
Medical uses
Ribavirin is used primarily to treat hepatitis C and viral hemorrhagic fevers (which is an orphan indication in most countries).[4] In this former indication the oral (capsule or tablet) form of ribavirin is used in combination with pegylated interferon alfa.[5][6][7][8] Including in people coinfected with hepatitis B, HIV and in the pediatric population.[7][9][10] Statins may improve this combination's efficacy in treating hepatitis C.[11] 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.[12][13][14][15] 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.[16]
It has been used (in combination with ketamine, midazolam, and amantadine) in treatment of rabies.[17]
Experimental data indicate that ribavirin may have useful activity against Canine distemper.[18] 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.[19] Another study found that ribavirin potentiated the antiviral effect of acyclovir.[20]
There has also been some interest in its possible use as a treatment for cancers, especially acute myeloid leukemia.[21][22]
Adverse effects
See also: List of adverse effects of ribavirin
Ribavirin should not be given with zidovudine because of the increased risk of anemia;[23] concurrent use with didanosine should likewise be avoided because of an increased risk of mitochondrial toxicity.[24]
Mechanisms of action
RNA viruses
Ribavirin's carboxamide 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.[25][26]
DNA viruses
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.[27]
History
In 1972 it was reported that ribavirin was active against a variety of RNA and DNA viruses in culture and in animals, without undue toxicity.[28]
Derivatives
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.[29] Note that two natural products were already known with this imidazole riboside structure: substitution at the 5' carbon with OH results in pyrazomycin/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.
Taribavirin (viramidine)
Main article: 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.,[30] 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. Viramidine, however, has useful properties of less erythrocyte-trapping and better liver-targeting than ribavirin. The first property is due to viramidine'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. Viramidine is in phase III human trials and may one day be used in place of ribavirin, at least against certain kinds of viral hepatitis. Viramidine's slightly superior toxicological properties may eventually cause it to replace ribavirin in all uses of ribavirin.[31]
See also
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Pharmacology portal |
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Viruses portal |
References
- ^ a b c d e "PRODUCT INFORMATION REBETOL® (RIBAVIRIN) CAPSULES" (PDF). TGA eBusiness Services. Merck Sharp & Dohme (Australia) Pty Limited. 29 April 2013. Retrieved 23 February 2014.
- ^ a b Carter, John; Saunders, Venetia (2007). Virology, Principles and Applications. John Wiley & Sons. ISBN 978-0-470-02386-0.
- ^ "WHO Model List of Essential Medicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
- ^ "Rebetol, Ribasphere (ribavirin) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 23 February 2014.
- ^ Paeshuyse, J; Dallmeier, K; Neyts, J (December 2011). "Ribavirin for the treatment of chronic hepatitis C virus infection: a review of the proposed mechanisms of action.". Current Opinion in Virology 1 (6): 590–8. doi:10.1016/j.coviro.2011.10.030. PMID 22440916.
- ^ Flori, N; Funakoshi, N; Duny, Y; Valats, JC; Bismuth, M; Christophorou, D; Daurès, JP; Blanc, P (March 2013). "Pegylated interferon-α2a and ribavirin versus pegylated interferon-α2b and ribavirin in chronic hepatitis C : a meta-analysis.". Drugs 73 (3): 263–77. doi:10.1007/s40265-013-0027-1. PMID 23436591.
- ^ a b Druyts, E; Thorlund, K; Wu, P; Kanters, S; Yaya, S; Cooper, CL; Mills, EJ (April 2013). "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.". Clinical Infectious Diseases 56 (7): 961–7. doi:10.1093/cid/cis1031. PMID 23243171.
- ^ Zeuzem, S; Poordad, F (July 2010). "Pegylated-interferon plus ribavirin therapy in the treatment of CHC: individualization of treatment duration according to on-treatment virologic response.". Current Medical Research and Opinion 26 (7): 1733–43. doi:10.1185/03007995.2010.487038. PMID 20482242.
- ^ Liu, JY; Sheng, YJ; Hu, HD; Zhong, Q; Wang, J; Tong, SW; Zhou, Z; Zhang, DZ; Hu, P; Ren, H (6 September 2012). "The influence of hepatitis B virus on antiviral treatment with interferon and ribavirin in Asian patients with hepatitis C virus/hepatitis B virus coinfection: a meta-analysis." (PDF). Virology Journal 9: 186. doi:10.1186/1743-422X-9-186. PMC 3511228. PMID 22950520.
- ^ Basso, M; Parisi, SG; Mengoli, C; Gentilini, V; Menegotto, N; Monticelli, J; Nicolè, S; Cruciani, M; Palù, G (July–August 2013). "Sustained virological response and baseline predictors in HIV-HCV coinfected patients retreated with pegylated interferon and ribavirin after failing a previous interferon-based therapy: systematic review and meta-analysis.". HIV Clinical Trials 14 (4): 127–39. doi:10.1310/hct1404-127. PMID 23924585.
- ^ Zhu, Q; Li, N; Han, Q; Zhang, P; Yang, C; Zeng, X; Chen, Y; Lv, Y; Liu, X; Liu, Z (June 2013). "Statin therapy improves response to interferon alfa and ribavirin in chronic hepatitis C: a systematic review and meta-analysis.". Antiviral Research 98 (3): 373–9. doi:10.1016/j.antiviral.2013.04.009. PMID 23603497.
- ^ Steckbriefe seltener und importierter Infektionskrankheiten [Characteristics of rare and imported infectious diseases]. Berlin: Robert Koch Institute. 2006. ISBN 3-89606-095-3.
- ^ Ascioglu, S; Leblebicioglu, H; Vahaboglu, H; Chan, KA (June 2011). "Ribavirin for patients with Crimean-Congo haemorrhagic fever: a systematic review and meta-analysis." (PDF). The Journal of Antimicrobial Chemotherapy 66 (6): 1215–22. doi:10.1093/jac/dkr136. PMID 21482564.
- ^ Bausch, DG; Hadi, CM; Khan, SH; Lertora, JJ (15 December 2010). "Review of the literature and proposed guidelines for the use of oral ribavirin as postexposure prophylaxis for Lassa fever." (PDF). Clinical Infectious Diseases 51 (12): 1435–41. doi:10.1086/657315. PMID 21058912.
- ^ Soares-Weiser, K; Thomas, S; Thomson, G; Garner, P (13 July 2010). "Ribavirin for Crimean-Congo hemorrhagic fever: systematic review and meta-analysis." (PDF). BMC Infectious Diseases 10: 207. doi:10.1186/1471-2334-10-207. PMC 2912908. PMID 20626907.
- ^ Ventre, K; Randolph, AG (24 January 2007). "Ribavirin for respiratory syncytial virus infection of the lower respiratory tract in infants and young children" (PDF). The Cochrane Database of Systematic Reviews (1): CD000181. doi:10.1002/14651858.CD000181.pub3. PMID 17253446. Retrieved 15 April 2014.
- ^ Hemachudha, T; Ugolini, G; Wacharapluesadee, S; Sungkarat, W; Shuangshoti, S; Laothamatas, J (May 2013). "Human rabies: neuropathogenesis, diagnosis, and management.". Lancet Neurology 12 (5): 498–513. doi:10.1016/S1474-4422(13)70038-3. PMID 23602163.
- ^ Elia G, Belloli C, Cirone F, et al. (February 2008). "In vitro efficacy of ribavirin against canine distemper virus". Antiviral Res. 77 (2): 108–13. doi:10.1016/j.antiviral.2007.09.004. PMID 17949825.
- ^ Bierman, SM; Kirkpatrick W, Fernandez H (1981). "Clinical efficacy of ribavirin in the treatment of genital herpes simplex virus infection". Chemotherapy 27 (2): 139–45. doi:10.1159/000237969. PMID 7009087. Retrieved 2011-05-13.
- ^ Pancheva, SN (Sep 1991). "Potentiating effect of ribavirin on the anti-herpes activity of acyclovir". Antiviral Res. 16 (2): 151–61. doi:10.1016/0166-3542(91)90021-I. PMID 1665959. Retrieved May 13, 2011.
- ^ Kast, RE (November–December 2002). "Ribavirin in cancer immunotherapies: controlling nitric oxide helps generate cytotoxic lymphocyte." (PDF). Cancer Biology & Therapy 1 (6): 626–30. PMID 12642684.
- ^ Borden, KL; Culjkovic-Kraljacic, B (October 2010). "Ribavirin as an anti-cancer therapy: acute myeloid leukemia and beyond?" (PDF). Leukemia & Lymphoma 51 (10): 1805–15. doi:10.3109/10428194.2010.496506. PMC 2950216. PMID 20629523.
- ^ Alvarez D, Dieterich DT, Brau N, Moorehead L, Ball L, Sulkowski MS (2006). "Zidovudine use but not weight-based ribavirin dosing impacts anaemia during HCV treatment in HIV-infected persons". J Viral Hepat 13 (10): 683–89. doi:10.1111/j.1365-2893.2006.00749.x. PMID 16970600.
- ^ Bani-Sadr F, Carrat F, Pol S, et al. (2005). "Risk factors for symptomatic mitochondrial toxicity in HIV/hepatitis C virus-coinfected patients during interferon plus ribavirin-based therapy". J Acquir Immune Defic Syndr 40 (1): 47–52. doi:10.1097/01.qai.0000174649.51084.46. PMID 16123681.
- ^ Ortega-Prieto, Ana M.; Sheldon, Julie; Grande-Pérez, Ana; Tejero, Héctor; Gregori, Josep; Quer, Josep; Esteban, Juan I.; Domingo, Esteban; Perales, Celia (2013). "Extinction of Hepatitis C Virus by Ribavirin in Hepatoma Cells Involves Lethal Mutagenesis". In Vartanian, Jean-Pierre. PLoS ONE 8 (8): e71039. doi:10.1371/journal.pone.0071039. PMC 3745404. PMID 23976977.
- ^ Crotty S, Cameron C, Andino R (February 2002). "Ribavirin's antiviral mechanism of action: lethal mutagenesis?". J. Mol. Med. 80 (2): 86–95. doi:10.1007/s00109-001-0308-0. PMID 11907645.
- ^ Leyssen P, De Clercq E, Neyts J (April 2006). "The anti-yellow fever virus activity of ribavirin is independent of error-prone replication". Mol. Pharmacol. 69 (4): 1461–7. doi:10.1124/mol.105.020057. PMID 16421290.
- ^ Sidwell, R. W.; Huffman, J. H.; Khare, G. P.; Allen LB, L. B.; Witkowski, J. T.; Robins, R. K. (1972). "Broad-Spectrum Antiviral Activity of Virazole: 1-f8- D-Ribofuranosyl- 1,2,4-triazole- 3-carboxamide". Science 177 (4050): 705–6. doi:10.1126/science.177.4050.705. PMID 4340949.
- ^ Smith RA & Kirkpatrick W (eds.) (1980). "Ribavirin: structure and antiviral activity relationships". Ribavirin: A Broad Spectrum Antiviral Agent. New York: Academic Press. pp. 1–21.
- ^ Witkowski JT, Robins RK, Khare GP, Sidwell RW (August 1973). "Synthesis and antiviral activity of 1,2,4-triazole-3-thiocarboxamide and 1,2,4-triazole-3-carboxamidine ribonucleosides". J. Med. Chem. 16 (8): 935–7. doi:10.1021/jm00266a014. PMID 4355593.
- ^ Sidwell RW, Bailey KW, Wong MH, Barnard DL, Smee DF (October 2005). "In vitro and in vivo influenza virus-inhibitory effects of viramidine". Antiviral Res. 68 (1): 10–7. doi:10.1016/j.antiviral.2005.06.003. PMID 16087250.
External links
- http://www.hepcassoc.org/news/article39.html
- http://www.jac.oxfordjournals.org/cgi/content/full/52/4/543
- http://www.hepatitiscentral.com/hcv/ribavirin/info.html
- http://aidsinfo.nih.gov/drugs/htmldrug_tech.asp?int_id=0028
- http://www.jac.oxfordjournals.org/cgi/reprint/dki405v1
- Information on Ribavirin
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DNA virus antivirals (primarily J05, also S01AD and D06BB)
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| Baltimore I |
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Herpesvirus
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DNA-synthesis
inhibitor
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TK activated
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Purine analogue
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- guanine (Aciclovir#/Valaciclovir
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Pyrimidine analogue
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Not TK activated
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Other
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Poxviridae
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Nucleic acid inhibitors
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Interferon
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- Interferon alfa 2b
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Multiple/unknown
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- Ribavirin#/Taribavirin†
- Moroxydine
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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cutn/syst (hppv/hiva, infl/zost/zoon)/epon
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drug (dnaa, rnaa, rtva, vacc)
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RNA virus antivirals (primarily J05, also S01AD and D06BB)
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| Hepatitis C |
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| Multiple/general |
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Interferon
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- Interferon alfa 2b
- Peginterferon alfa-2a
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Multiple/unknown
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- Ribavirin#/Taribavirin†
- Moroxydine
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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cutn/syst (hppv/hiva, infl/zost/zoon)/epon
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drug (dnaa, rnaa, rtva, vacc)
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