Oseltamivir, neuraminidase inhibitors

Two neuraminidase inhibitors (oseltamivir carboxylate and zanamivir) are approved for prevention and treatment of infections with both influenza A and B viruses as discussed in chapter by Itzstein and Thomson, this volume. Oseltamivir carboxylate (OC) has gained most use because it can be taken orally, whereas the current formulation of zanamivir has to be inhaled. In addition, the WHO reconunends oseltamivir for treatment of clinically confirmed cases of H5N1 and for post-exposme prophylaxis to control recent H5N1 avian influenza outbreaks. 

The two classes of antiviral drugs available for treatment of influenza are the same as those available for prophylaxis and include the adamantanes, amantadine and rimantadine, and the neuraminidase inhibitors, oseltamivir and zanamivir. Because of widespread resistance to the adamantanes among influenza A viruses in the United States, amantadine and rimantadine are not recommended for treatment of influenza until susceptibility can be reestablished. 

Currently, two classes of drugs are available with antiviral activity against influenza viruses inhibitors of the ion channel activity of the M2 membrane protein, amantadine and rimantadine, and the neuraminidase inhibitors oseltamivir, and zanamivir. H5N1 viruses isolated from poultry and humans in Thailand and Viet Nam in 2004 invariably showed an amantadine-resistance indicating that amantadine treatment is not an option during the ongoing outb-treak in South-East Asia. 

S. Abrecht, P. Harrington, H. Iding, M. Karpf, R. Trussardi, B. Wirz, and U. Zutter, The synthetic development of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu) A challenge for synthesis process research, Chimia, 58 (2004) 621-929. 

Karpf, M. et al. New, Azide-Free Transformation of Epoxides into 1,2-Diamino Compounds Synthesis of the Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu). 3.4.4 2001 [135]... 

There has been much recent anxious speculation that the bird flu virus will mutate to a form that will spread from person to person. A worldwide influenza epidemic, at worst comparable to that which followed the Great War, could well be the net result of such an event. The efficacy of the first carbocychc neuraminidase inhibitor, oseltamivir (34), known famiharly... 

Treanor JJ, Hayden FG, Vrooman PS, Barbarash R, Bettis R, Riff D, Singh S, Kinnersley N, Ward P, Mills RG. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA 2000 283(8) 1016-24. 

Hayden EG, Atmar RL, Schilling M, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. New Engl J Med 1999 341 1336-1343. 

Scheme 6 Structure of the potent neuraminidase inhibitors oseltamivir phosphate 18 (Tamiflu ) and zanamivir 19 (Relenza ).

Ishikawa H, Suzuki T, Orita H, Uchimaru T, Hayashi Y. High-yielding synthesis of the anti-influenza neuraminidase inhibitor (—)-oseltamivir by two one-pot sequences. Chem. Eur. J. 2010 16(42) 12616-12626. 

Neuraminidase inhibitors are the major class of drugs to treat or to prevent the infection with influenza viruses. Currently, two neuraminidase inhibitors are available, zanamivir and oseltamivir, which block the release of new influenza vims from infected host cells and thereby stop the spread of infection. The enzyme neuraminidase is a surface glycoprotein present on all influenza viruses. There are nine influenza neuraminidase sub-types known of which subtypes N1 and N2 appear to be the most important ones. Neuraminidase inhibitors are effective against all neuraminidase subtypes. The activity of the neuraminidase is required for the newly... 

Abed Y, Nehmd B, Baz M, Boivin G (2008) Activity of the neuraminidase inhibitor A-315675 against oseltamivir-resistant influenza neuraminidases of N1 and N2 subtypes. Antiviral Res 77 163-166... 

Two classes of inhibitors for influenza virus are currently available (Hayden 2006). The M2 proton channel inhibitors amantadine and rimantadine and the neuraminidase (NA) inhibitors oseltamivir carboxylate and zanamivir. Chapter 5 provides more details about the class of NA inhibitors. 

Oseltamivir and zanamivir are neuraminidase inhibitors that have activity against both influenza A and influenza B viruses. When administered within 48 hours of the onset of illness, oseltamivir and zanamivir may reduce the duration of illness by approximately 1 day versus placebo. 

NEURAMINIDASE INHIBITORS FOR INFLUENZA OSELTAMIVIR PHOSPHATE (TAMIFLU ) AND ZANAMIVIR (RELENZA )... 

Zanamivir (Relenza) is a neuraminidase inhibitor with activity against influenza A and B strains. Like oseltamivir, zanamivir is a reversible competitive antagonist of viral neuraminidase. It inhibits the release of progeny virus, causes viral aggregation at the cell surface, and impairs viral movement through respiratory secretions. Resistant variants with hemagglutinin and/or neuraminidase mutations have been produced in vivo however, clinical resistance to zanamivir is quite rare at present. 

L D. The conversion of penciclovir to its active form requires initial monophosphorylation by viral thymidine kinases, then conversion to its active triphosphate form by cellular enzymes. Thus, the concentration of penciclovir triphosphate is particularly high in cells infected with its target viruses (e.g., HSV, VZV, HBV). Foscarnet is a pyrophosphate analogue that does not require activation. Oseltamivir is a neuraminidase inhibitor that is con-... 

Neuraminidase is an essential viral glycoprotein for virus replication and release. The neuraminidase inhibitors zanamivir and oseltamivir have recently been approved for the treatment of acute uncomplicated influenza infection. When a 5-day course of therapy is initiated within 36-48 hours after the onset of symptoms, use of either agent shortens the severity and duration of illness and may decrease the incidence of respiratory complications in children and adults. Unlike amantadine and rimantidine, zanamivir and oseltamivir have activity against both influenza A and influenza B. Zanamivir is administered via oral inhaler. The compound displays poor oral bioavailability, limited plasma protein binding, rapid renal clearance, and absence of significant metabolism. Nasal and throat discomfort may occur—as well as bronchospasm in patients with reactive airway disease. 

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