Ribavirin

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Ribavirin
Ribavirin.svg
Ribavirin ball-and-stick.png
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 YesY
ATC code J05AB04
PubChem CID 37542
DrugBank DB00811
ChemSpider 34439 YesY
UNII 49717AWG6K YesY
KEGG D00423 YesY
ChEMBL CHEMBL1643 YesY
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
 YesY (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]

Medical uses[edit]

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[edit]

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[edit]

RNA viruses[edit]

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[edit]

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[edit]

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[edit]

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)[edit]

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[edit]

References[edit]

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External links[edit]