Ribavirin
Synonym(s):1-β-D -Ribofuranosyl-1,2,4-triazole-3-carboxamide;1-β-D-Ribofuranosyl-1,2,4-triazole-3-carboxamide, Virazole;Ribavirin;Ribavirin - CAS 36791-04-5 - Calbiochem
- CAS NO.:36791-04-5
- Empirical Formula: C8H12N4O5
- Molecular Weight: 244.21
- MDL number: MFCD00058564
- EINECS: 636-825-3
- SAFETY DATA SHEET (SDS)
- Update Date: 2024-12-18 13:37:16
What is Ribavirin?
Absorption
Ribavirin is reported to be rapidly and extensively absorbed following oral administration. The average time to reach Cmax was 2 hours after oral administration of 1200 mg ribavirin . The oral bioavailability is 64% following a single oral dose administration of 600mg ribavirin .
Toxicity
Rivabirin and PEG-Interferon Alfa-2A dual therapy is associated with flu-like symptoms, depression, suicide, insomnia, irritability, relapse of drug abuse/overdose, hepatic decompensation in 2% of HIV co-infected patients and bacterial infections each occurring at a frequency of less than 1%. Ribavirin-induced anemia is a dose-dependent adverse effect where reduced hemoglobin levels can be seen within the first 1-2 weeks in therapy. The mechanism of ribavirin-induced anemia has been shown to involve reductions in reticulocyte counts and erythrocyte Na-K pump activity, and increases in K-Cl cotransport, membrane bound IgG, and C3, and erythrocyte band 3 . Oral LD50 in rats is 2700 mg/kg. Intraperitoneal LD50 in mouse is 1300 mg/kg. Potential carcinogenic effects of ribavirin to humans cannot be yet excluded as it demonstrates mutagenic activity in the in vitro mouse lymphoma assay.
Description
Ribavirin is a clinically useful antiviral medication for Hepatitis C, viral hemorrhagic fevers and other RNA and DNA viruses. The exact mechanism of its antiviral activity is uncertain. Various proposals include inhibition of viral polymerase1, RNA mutagenesis2, and inosine monophosphate dehydrogenase (IMPDH) inhibition3. Sensitizes tumor cells to anticancer agents 5-fluorouracil5 and doxorubicin6 via inhibition of eIF4E. Displays efficacy against atypical teratoid/rhabdoid tumors7 and inhibits glioma cell growth8.
Chemical properties
Colourless Solid
The Uses of Ribavirin
Ribavirin is a guanosine analog with antiviral properties against DNA and RNA viruses, including respiratory syncytial virus, hepatitis C, and influenza. It acts as a prodrug that can be activated by either mono- or tri-phosphorylation by cellular kinases. These phosphorylated derivatives of ribavirin have diverse effects on both cellular and viral enzymes, resulting in suppression of viral replication.
The Uses of Ribavirin
Purine nucleoside analog; inhibits inosine monophosphate dehydrogenase (IMPDH). Used as an antiviral agent.
The Uses of Ribavirin
aldosterone antagonist; antifibrogenic
The Uses of Ribavirin
anti-infective, anti-fungal
The Uses of Ribavirin
A broad spectrum antiviral nucleoside and inhibitor of inosine monophosphate dehydrogenase.
Background
Producing a broad-spectrum activity against several RNA and DNA viruses, Ribavirin is a synthetic guanosine nucleoside and antiviral agent that interferes with the synthesis of viral mRNA. It is primarily indicated for use in treating hepatitis C and viral hemorrhagic fevers. HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients . It is reported that ribavirin might be only effective in early stages of viral hemorrhagic fevers including Lasser fever, Crimean-Congo hemorrhagic fever, Venezuelan hemorrhagic fever, and Hantavirus infection. Ribavirin is a prodrug that is metabolized into nucleoside analogs that blocks viral RNA synthesis and viral mRNA capping. Before the development of newer drugs, ribavirin and Peginterferon alfa-2a/Peginterferon alfa-2b dual therapy was considered the first-generation and standard antiviral treatment . The dual therapy was administered for 48 weeks in patients with genotype 1, 4, 5, and 6, and 24 weeks in patients with genotype 2 and 3 . Newer drugs developed as Hepatitis C viral infection treatments can be used to reduce or eliminate the use of ribavirin, which are associated with serious adverse effects. They also improve therapeutic efficacy in patients with failed Peginterferon alfa-2a/Peginterferon alfa-2b and ribavirin-based therapy. The potential use of ribavirin as a treatment for acute myeloid leukemia is currently under investigation.
According to 2017 American Association for the Study of Liver Diseases (AASLD) and 2015 consensus guidelines from the Canadian Association for the Study of the Liver (CASL), ribavirin is typically used as an adjunct therapy to various first-line and second-line combination therapies recommended for each genotypes. Ribavirin is added to decrease relapse rates by accelerating viral clearance early in the treatment course . When used to treat Hepatitis C virus (HCV) infections, it is always used as a part of combination therapies as ribavirin monotherapy is not efficacious in the treatment of chronic hepatitis C infection . Additionally, including ribavirin in the regimen can increase the risk of anemia.
In HCV genotye 1/2/3/4/5/6 patients, ribavirin can be used in combination therapy involving Daclatasvir and Sofosbuvir, Eplusa (Sofosbuvir, Velpatasvir), Harvoni (Sofosbuvir, Ledipasvir), Simeprevir and Sofosbuvir, Viekira Pak (Ombitasvir, Paritaprevir, Ritonavir, Dasabuvir), Technivie (Ritonavir, Ombitasvir, Paritaprevir) and Zepatier (Elbasvir, Grazoprevir). Addition of weight-based ribavirin to Technivie therapy increased sustained virologic response after 12 weeks of daily therapy (SVR12) from 90% to 97% in patients with HCV genotype 1a and 90.9% to 100% in HCV genotype 4 patients . Zepatier therapy along with ribavirin improved SVR in HCV genotype 5 patients. Combination therapy of ribavirin and Peginterferon alfa-2a results in the SVR of 44% in patients with genotype 1 infection and 70% in patients with genotype 2-6. The inclusion of ribavirin in the combination therapies depend on individual patient's profile, for example if HCV genotype 3 patient has a Y93H genetic variant and compensated cirrhosis.
What are the applications of Application
Ribavirin is a broad spectrum antiviral nucleoside and inhibitor of inosine monophosphate dehydrogenase
Indications
Indicated for the treatment of chronic Hepatitis C virus (HCV) infection in combination with other antiviral agents with the intent to cure or achieve a sustained virologic response (SVR). Typically added to improve SVR and reduce relapse rates .
The addition of ribavirin in Technivie therapy indicated for treating HCV genotype 1a and 4 infections is recommended in patients with or without cirrhosis.
Resistance: viral genetic determinants resulting in variable response to ribavirin therapy has not been yet determined.
Definition
ChEBI: A 1-ribosyltriazole that is the 1-ribofuranosyl derivative of 1,2,4-triazole-3-carboxamide. An inhibitor of HCV polymerase.
Indications
Ribavirin is a synthetic guanosine analogue that possesses broad antiviral inhibitory activity against many viruses, including influenza A and B, parainfluenza,RSV, HCV, HIV-1, and various herpesviruses, arenaviruses, and paramyxoviruses. Its exact mechanism of action has not been fully elucidated; however, it appears to inhibit the synthesis of viral mRNA through an effect on nucleotide pools. Following absorption, host cell enzymes convert ribavirin to its monophosphate, diphosphate, and triphosphate forms. Ribavirin monophosphate inhibits the guanosine triphosphate (GTP) synthesis pathway and subsequently inhibits many GTP-dependent processes. Ribavirin triphosphate inhibits the 5 capping of viral mRNA with GTP and specifically inhibits influenza virus RNA polymerase. Ribavirin may also act by increasing the mutation rate of RNA viruses, leading to the production of nonviable progeny virions. Ribavirin resistance has not been documented in clinical isolates.
brand name
Copegus (Roche); Rebetol (Schering); Virazole (Valeant).
Acquired resistance
Development of resistant virus strains has not been demonstrated.
General Description
White powder. Exists in two polymorphic forms.
General Description
Ribavirin is 1-β-D-ribofuranosyl-1,2,4-thiazole-3-carboxamide.The compound is a purine nucleoside analog with amodified base and a D-ribose sugar moiety.
Ribavirin inhibits the replication of a very wide variety ofRNA and DNA viruses,68 including orthomyxoviruses,paramyxoviruses, arenaviruses, bunyaviruses, herpesviruses,adenoviruses, poxvirus, vaccinia, influenza virus(types A and B), parainfluenza virus, and rhinovirus. In spiteof the broad spectrum of activity of ribavirin, the drug hasbeen approved for only one therapeutic indication—thetreatment of severe lower respiratory infections caused byRSV in carefully selected hospitalized infants and youngchildren.
Air & Water Reactions
Water soluble.
Reactivity Profile
Ribavirin may be sensitive to prolonged exposure to light.
Hazard
Mildly toxic by ingestion. An experimental teratogen.
Fire Hazard
Flash point data for Ribavirin are not available; however, Ribavirin is probably combustible.
Pharmaceutical Applications
A synthetic nucleoside. It is neither a classic pyrimidine nor a purine, but stereochemical studies indicate that it is a guanosine analog. It is usually formulated for administration by inhalation, but oral and intravenous preparations are also used.
Biochem/physiol Actions
Antiviral agent used against a wide variety of human viral infections, in particular, chronic hepatitis?C, HIV, and adenovirus. Its metabolite, ribavirin 5′-phosphate, is an inhibitor of inosine monophosphate (IMP) dehydrogenase, but many other mechanisms of action are also supported with experimental evidence.
Mechanism of action
Ribavirin, a guanosine analogue, has broad-spectrum antiviral activity against both DNA and RNA viruses. It is phosphorylated by adenosine kinase to the triphosphate, resulting in the inhibition of viral specific RNA polymerase, disrupting messenger RNA and nucleic acid synthesis.
Pharmacokinetics
Ribavirin mediates direct antiviral activity against a number of DNA and RNA viruses by increasing the mutation frequency in the genomes of several RNA viruses. It is a member of the nucleoside antimetabolite drugs that interfere with duplication of the viral genetic material. The drug inhibits the activity of the enzyme RNA dependent RNA polymerase, due to its resemblence to building blocks of the RNA molecules.
Pharmacokinetics
Oral absorption: 36–46%
Cmax 3 mg/kg oral: 4.1–8.2 μmol/L after 1–1.5 h
600 mg intravenous: 43.6 μmol/L end infusion
Plasma half-life: c. 24 h
Volume of distribution: 647 L
Plasma protein binding: <10%
Absorption
It is rapidly absorbed after oral administration. Mean peak concentrations after 1 week of oral doses of 200, 400 and 800 mg every 8 h were 5.0, 11.1 and 20.9 μmol/L, respectively. Trough levels 9–12 h after the end of 2 weeks’ therapy were 5.1, 13.2 and 18.4 μmol/L, respectively, indicating continued accumulation of the drug. Drug was still detectable 4 weeks later. Mean peak plasma concentrations after intravenous doses of 600, 1200 and 2400 mg were 43.6, 72.3 and 160.8 μmol/L, respectively; at 8 h the mean plasma concentrations were 2.1, 5.6 and 10.2 μmol/L. Aerosolized doses (6 g in 300 mL distilled water) are generally administered at a rate of 12–15 mL/h using a Collison jet nebulizer, the estimated dosage being 1.8 mg/kg per h for infants and 0.9 mg/kg per h for adults. When administered by small particle aerosol for 2.5–8 h, plasma concentrations ranged from 0.44 to 8.7 μmol/L.
Metabolism and excretion
It is rapidly degraded by deribosylation or amide hydrolysis, and together with its metabolites is slowly eliminated by the kidney. About 50% of the drug or its metabolites appear in the urine within 72 h and 15% is excreted in the stools. The remainder seems to be retained in body tissues, principally in red blood cells, which concentrate the drug or metabolites to a peak at 4 days, with a half-life of around 40 days. After intravenous administration 19.4% of the dose was eliminated during the first 24 h (compared with 7.3% after an oral dose), the difference reflecting the bioavailability.
Pharmacology
Oral and intravenous ribavirin are associated with additional adverse effects.When given via these routes, ribavirin can produce hemolytic anemia that is reversible following dosage reduction or cessation of therapy. When given in combination with interferon- , ribavirin increases the incidence of many of its side effects, such as fatigue, nausea, insomnia, depression, and anemia, and may cause fatal or nonfatal pancreatitis. Ribavirin is mutagenic, teratogenic, and embryotoxic in animals at doses below the therapeutic level in humans. It is contraindicated in pregnant women and in the male partners of pregnant women. Women of childbearing potential and male partners of these women must use two effective forms of contraception during ribavirin treatment and for 6 months post therapy. Pregnant women should not directly care for patients receiving ribavirin.
Clinical Use
RSV infections in infants (by nebulizer) in emergency situations
(i.e. transplant recipients)
Lassa fever
Hepatitis C (in combination with interferon-α)
Use in RSV pneumonia in infants is no longer routine. It
reduces mortality from Hantaan virus, the agent responsible
for hemorrhagic fever with renal syndrome.
Clinical Use
Ribavirin aerosol (Virazole) is indicated in the treatment
of high-risk infants and young children with severe
bronchiolitis or pneumonia due to RSV infection.
Treatment is most effective if begun within 3 days of the
onset of symptoms.
Although ribavirin monotherapy is ineffective
against HCV, oral ribavirin in combination with interferon-α
(Rebatron) is approved for this indication and is
effective in patients resistant to interferon therapy
alone. Intravenous ribavirin may be useful in the therapy
of Hantaan virus infection, Crimean or Congo virus
hemorrhagic fever, Lassa fever, and severe adenovirus
infection.
Side Effects
It is generally well tolerated, though adverse reactions appear
to be related to dose and duration of therapy. Minor adverse
reactions include metallic taste, dry mouth sensation and
increased thirst, flatulence, fatigue and CNS complaints,
including headache, irritability and insomnia. Daily doses of
1 g may cause unconjugated bilirubin levels to double and
the reticulocyte count to increase. Hemoglobin concentrations
may decrease with treatment or higher dosages; with
doses of 3.9–12.6 g per day, a drop in hemoglobin was noted
by days 7–13 of treatment, which was generally ‘rapidly’
reversible
on withdrawal of the drug, but in some instances
necessitated blood transfusion.
Aerosol administration of about 2 g in 36 or 39 h during
3 days is well tolerated, does not affect results of pulmonary
function tests, and seems non-toxic.
It is both teratogenic and embryotoxic in laboratory animals,
so precautions must be observed in women of childbearing
age.
Side Effects
Most adverse effects associated with aerosol ribavirin are local. Pulmonary function may decline if aerosol ribavirin is used in adults with chronic obstructive lung disease or asthma. Deterioration of pulmonary and cardiovascular function has also been seen in severely ill infants given this preparation. Rash, conjunctivitis, and rare cases of anemia have been reported. Health care workers exposed to aerosol ribavirin during its administration have reported adverse effects including headache, conjunctivitis, rash, and rarely, bronchospasm.
Synthesis
Ribavirin, 1-|?-D-ribofuranosyl-1H-1,2,4-triazol-3-carboxamide (36.1.28), is synthesized by reacting methyl ester of 1,2,4-triazol-3-carboxylic acid with O-1,2,3, 5-tetraacetyl-|?-D-ribofuranose to make methyl ester of 1-O-2,3,5-tetraacetyl-|?-D-ribofuranosyl-1,2,4-triazol-3-carboxylic acid (36.1.27), which is treated with an ammonia solution of methanol to simultaneously dezacylate the carbohydrate part and amidation of the carboxyl part of the product to give ribavirin.
Drug interactions
Potentially hazardous interactions with other drugs
Antivirals: effects possibly reduced by abacavir;
increased risk of toxicity with stavudine; increased
side effects with didanosine - avoid; increased risk of
anaemia with zidovudine - avoid.
Azathioprine: possibly enhances myelosuppressive
effects of azathioprine.
Metabolism
First and as a step required for activation, ribavirin is phosphorylated intracellularly by adenosine kinase to ribavirin mono-, di-, and triphosphate metabolites. After activation and function, ribavirin undergoes two metabolic pathways where it is reversibly phosphorlyated or degraded via deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite. In vitro studies indicate that ribavirin is not a substrate of CYP450 enzymes .
Metabolism
Ribavirin is metabolised by reversible phosphorylation
and a degradative pathway involving deribosylation and
amide hydrolysis to produce an active triazole carboxyacid
metabolite.
Ribavirin is mainly excreted in the urine as unchanged
drug and metabolites.
storage
+4°C
References
1) Bougie and Bisaillon (2003), Initial binding of the broad spectrum antiviral nucleoside ribavirin to the hepatitis C virus RNA polymerase; J. Biol. Chem. 278 52471 2) Crotty et al. (2000), The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen; Nat. Med. 6 1375 3) Zhou et al. (2003), The effect of ribavirin and IMPDH inhibitors on hepatitis C virus subgenomic replicon RNA; Virology 310 333 4) Couee and Tipton (1990), Inhibition of ox brain glutamate by perphenazine; Biochem. Pharmacol. 39 1167 5) Hu et al. (2019), Ribavirin sensitizes nasopharyngeal carcinoma to 5-fluorouracil through suppressing 5-fluorouracil-induced ERK-dependent-elF4E activation; Biochem. Biophys. Res. Commun. 513 862 6) Tan et al. (2018), Ribavirin augments doxorubicin’s efficacy in human hepatocellular carcinoma through inhibiting doxorubicin-induced elF4E activation; J. Biochem. Mol. Toxicol. 32(1) e22007 7) Casaos et al. (2018), Ribavirin as a potential therapeutic for atypical teratoid/rhabdoid tumors; Oncotarget; 9 8054 8) Volpin et al. (2017) Use of an anti-viral drug, Ribavirin, as an anti-glioblastoma therapeutic; Oncogene, 36 3037
Properties of Ribavirin
Melting point: | 174-176°C |
Boiling point: | 387.12°C (rough estimate) |
alpha | D25 -36.5° (c = 1 in water); D20 -38° (c = 1 in water) |
Density | 1.4287 (rough estimate) |
refractive index | -36 ° (C=1, H2O) |
storage temp. | 2-8°C |
solubility | Freely soluble in water, slightly soluble in ethanol (96 per cent), slightly soluble or very slightly soluble in methylene chloride. It shows polymorphism (5.9). |
form | White solid |
pka | 12.95±0.70(Predicted) |
color | White |
Water Solubility | >=10 g/100 mL at 19 ºC |
Merck | 14,8198 |
Stability: | Stable for 1 year from date of purchase as supplied. Solutions in DMSO or distilled water may be stored at -20°C for up to 3 months. |
CAS DataBase Reference | 36791-04-5 |
EPA Substance Registry System | Ribavirin (36791-04-5) |
Safety information for Ribavirin
Signal word | Danger |
Pictogram(s) |
Health Hazard GHS08 |
GHS Hazard Statements |
H341:Germ cell mutagenicity |
Precautionary Statement Codes |
P201:Obtain special instructions before use. P308+P313:IF exposed or concerned: Get medical advice/attention. |
Computed Descriptors for Ribavirin
InChIKey | IWUCXVSUMQZMFG-AFCXAGJDSA-N |
Ribavirin manufacturer
Trimax bio sciences private ltd
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