Influenza virus ribavirin

Mode of action The mode of action has been studied only for the influenza viruses. Ribavirin is first converted to the 5 -phosphate derivatives, the major product being the compound ribavirin-triphosphate (RTP), which has been postulated to exert its antiviral action by inhibiting viral mRNA synthesis. [Note Rhinoviruses and enteroviruses, which contain preformed mRNA and do not need to synthesize mRNA in the host cell to initiate the infection, are relatively resistant to the action of ribavirin.]... 

It may be possible to increase the utility of our resources to treat influenza virus infection through combinations of antiviral agents with different modes of action (discussed in Cinatl et al. 2007a De Clercq and Neyts 2007). The sialidase inhibitors, for example, may be able to be used in conjunction with the adamantane-based M2 ion channel inhibitors (Govorkova et al. 2004 Ilyushina et al. 2006), with Ribavirin (Smee et al. 2002) or with non-influenza virus specific therapeutics such as anti-inflammatory drugs (Carter 2007). Combination therapy may also reduce the potential of resistance development (Ilyushina et al. 2006). 

Fig. 1.4 Hemagglutination assay results from the active fraction of the red alga Gigartina skottsbergii. a Red blood cells (RBCs) hemagglutinate in the presence of influenza virus top row) and with extract A4 -t- virus or extract A4 alone. The bottom two rows present the back titration of the virus used in this experiment, b In contrast to the other anti-influenza drugs (ribavirin, amantadine, rimantadine, and zanamivir) that do not induce hemagglutination of human as well as chicken RBCs, extract A4 does it in a dose-dependent manner...

Ribavirin inhibits (he replication of a very wide variety of RNA and DNA viruses, including orthomyxoviruses, paramyxoviruses, arenaviruses, bunyavirusc,s, herpesviruses, adenoviruses, poxvirus, vaccinia, influenza virus, parainfluenza virus, and rhinovirus. In spite of the broad spectrum of activity of ribavirin, the drug has been approved for only one therapeutic indication—(he treatment of severe lower respiratory infections caused by RSV in carefully selected hospitalized infants and young children. 

RNA viruses like HIV and the influenza virus use a naturally high mutation rate of their RNA polymerases with low fidelity for replication to avoid and escape most treatments and vaccines. A RNA virus tends to mistakenly insert ribavirin into newly synthesized copies of their RNA genome. But ribavirin adds so many extra mutations to the virus during the replication of its genetic materials, it induces a flood of mutations and thus pushes the virus into a kind of genetic meltdown. 

Amantadine blocks the attachment, penetration, and uncoating of influenza virus A zanamivir and oseltamivir inhibit influenza viruses A and B neuraminidase, promoting viral dumping and deceasing the chance of penetration. Ribavirin becomes phosphorylated and inhibits IMP dehydrogenase and RNA polymerase. It is used to treat respiratory syncytial virus, influenza A and B, Lassa fever,... 

The influenza virus is an RNA-(—)- virus and possesses its own RNA polymerase enzyme. The complete RNA genome codes for eight proteins - two structural (matrix) proteins M, and M2, haemagglutinin, and neuraminidase and four proteins involved in replication, three of which make up the polymerase enzyme. Substrates for this are the usual ribonucleosides and there has been some success with the use of nucleoside analogues as inhibitors of the enzyme. The drug ribavirin has been the most successful, although this has to be administered by aerosol. These days, its major use is for the treatment of infections caused by respiratory syncytial viruses (especially in children), since these can cause long-term morbidity. 

Respiratory virus infections (respiratory syncitial virus [RSV], parainfuenza viruses, influenza viruses and adenoviruses) are all highly contagious and symptomatic individuals should be isolated before virologic confirmation is available. To prevent progression of RSV from the upper to the lower respiratory tract, aerosolized ribavirin may be used alone or in combination with RSV-specific antibodies or palivizumab, an RSV-specific monoclonal antibody (Boeckh et al., 2001). 

Interferon alfa-2b is an immnnomodnlator. Interferon alfa-2b inhibits virus replication in virns-infected cells and suppresses cell proliferation althongh the exact mechanism of action of ribavirin is not know, it has antiviral inhibitory activity against respiratory syncytial virns, influenza virus, and herpes simplex virus. It is indicated in the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with alpha interferon or who have relapsed after alpha interferon therapy. 

Ribavirin has antiviral inhibitory activity in vitro against respiratory syncytial virus, influenza virus, and herpes simplex virus. 

Ribavirin monophosphate competitively inhibits cellular inosine-5 -phosphate dehydrogenase and interferes with the synthesis of guanosine triphosphate (GTP) and, thus, nucleic acid synthesis in general. Ribavirin triphosphate also competitively inhibits the GTP-dependent 5 -capping of viral messenger RNA and, specifically, influenza virus transcriptase activity. Ribavirin appears to have multiple sites of action, and some of these (e.g., inhibition of GTP synthesis) may potentiate others (e.g., inhibition of GTP-dependent enzymes). 

Intravenous and/or aerosol ribavirin has been used occasionally in treating severe influenza virus infection and in the treatment of immunosuppressedpatients with adenovirus, vaccinia, parainfluenza, or measles virus infections. Aerosolized ribavirin reduces duration of fever but has no other beneficial effects in influenza infections in hospitalized children. Intravenous ribavirin decreases mortality in Lassa fever and has been used in treating other arenavirus-related hemorrhagic fevers. Intravenous ribavirin is beneficial in hemorrhagic fever with renal syndrome owing to hantavirus infection but ineffective in hantavirus-associated cardiopulmonary syndrome or SARS. 

Smee DE, Bailey KW, Morrison AC, SidweU RW (2002) Combination treatment of influenza A virus infections in ceU culture and in mice with the cyclopentane neuraminidase inhibitor RWJ-270201 and ribavirin. Chemotherapy 48 88-93... 

Hirsutine (2-795), which belongs to the corynanthe subgroup of the indole alkaloids, was isolated from the plant Uncaria rhynchophylla MIQ and used for the preparation of the old Chinese folk medicine Kampo [397]. It is of pharmacological interest as it shows a strong inhibitory effect on the influenza A virus (subtype H3N2) with an EC50 = 0.40-0.57 pg ml. which is about 11- to 20-fold higher than that of the clinically used ribavirin [398]. 

Ribavirin is a synthetic analog of nucleosides. It is effective against many DNA and RNA viruses, such as viral influenza and herpes. The mechanism of its action is not completely known. However, it is highly likely that it is not the same for all viruses. It has been tried on a number of AIDS patients with various results. A synonym of this drag is virazoll. 

Ribavirin can inhibit the replication of both RNA and DNA viruses. It is a nucleoside analog which blocks guanosine monophosphate by inhibiting the enzyme inosine monodehydrogenase. Its main indication is severe respiratory syncytial virus infections in infants but it has also shown activity against influenza A and influenza B infections. It is administered by aerosol spray. No serious adverse effects occur when used as aerosol. 

Ribavirin is a synthetic guanosine analogue that possesses broad antiviral inhibitory activity against many viruses, including influenza A and B, parainfluenza, RS V, 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... 

In addition to oral administration for hepatitis C infection in combination with interferon alfa, aerosolized ribavirin is administered by nebulizer (20 mg/mL for 12-18 hours per day) to children and infants with severe respiratory syncytial virus (RSV) bronchiolitis or pneumonia to reduce the severity and duration of illness. Aerosolized ribavirin has also been used to treat influenza A and infections but has not gained widespread use. Systemic absorption is low (< 1%). Aerosolized ribavirin is generally well tolerated but may cause conjunctival or bronchial irritation. Health care workers should be protected against extended inhalation exposure. The aerosolized drug may precipitate on contact lenses. 

Intravenous ribavirin decreases mortality in patients with Lassa fever and other viral hemorrhagic fevers if started early. High concentrations inhibit West Nile virus in vitro, but clinical data are lacking. Clinical benefit has been reported in cases of severe measles pneumonitis and certain encephalitides, and continuous infusion of ribavirin has decreased virus shedding in several patients with severe lower respiratory tract influenza or parainfluenza infections. At steady state, cerebrospinal fluid levels are about 70% of those in plasma. 

The triazole ribofuranoside ribavirin (101) has been used clinically against influenza, parainfluenza and herpes infections with varying results, and imidazole ribofuranosides are active in vitro. The antibiotic pyrazofurin (102) inhibits the replication of many viruses and has also been tried as an anticancer drug. 

Antiviral Efficacy and Clinical Use. Ribavirin (Vira-zole) is active against several RNA and DNA viruses, including respiratory syncytial virus (RSV).106 Clinically, this drug is used to treat severe RSV pneumonia in infants and young children,106 and RSV in certain adult populations, including the elderly, people with cardiopulmonary problems, and people with a compromised immune system.29 Ribavirin may also be useful as a secondary agent in the treatment of influenza A and B in young adults. The combination of ribavirin and interferons (see section on Interferons, later) is often the treatment of choice in chronic hepatitis C infection.30 72... 

The alkaloids hirsutine (1) and its 3or-epimer dihydrocorynantheine (2a) belong to the corynanthe group of indole alkaloids. They have been isolated from the plant Uncaria rhynchophylla MIQ, which was used for the preparation of the old Chinese folk medicine kampo . Nowadays, 1 and related compounds attract great attention in medicine because of their growth inhibition of the influenza A subtype H3N2 virus. With an EC50 value of 0.40-0.57 ig/mL 1 has shown itself to be 10-20 times more active than the clinically used drug ribavirine (3).1,2 Furthermore, 1 is known for its antihypertensive and antiarrhythmic activity.3... 

A second class of antiviral compounds has been developed to inhibit viral replication by acting on the RNA polymerase (Fig. 17.3b). T-705 (favipiravir, 3) undergoes ribosylation and then phosphorylation and is believed to function similarly to a nucleobase in viral RNA replication [35,45], T-705 has been demonstrated to inhibit viral replication of influenza A, B, and C viruses, and recent studies have shown encouraging results toward it becoming a potential drug candidate [45,46], Compared to the most familiar polymerase inhibitor ribavirin (4), T-705 has a more favorable therapeutic index in preclinical test of toxicity [34, 35],... 

Antiviral spectrum Ribavirin is used in treating infants and young children infected with severe RSV infections. [Note It is not indicated for use in adults.] Favorable responses of acute hepatitis A virus and influenza A and B infections have also been reported. Ribavirin may reduce the mortality and viremia of Lassa fever. 

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