Disease relevance of zanamivir

• CONCLUSIONS: In adults with influenza A or B virus infections, direct administration of a selective neuraminidase inhibitor, zanamivir, to the respiratory tract is safe and reduces symptoms if begun early [1].
• CONTEXT: Influenza virus neuraminidase is thought to be essential for virus replication in humans; however, to date, available neuraminidase inhibitors are limited to zanamivir, which is topically administered [2].
• Safety and efficacy of once daily intranasal zanamivir in preventing experimental human influenza A infection [3].
• Furthermore, flu NA-mediated positive effect on HIV-1 biology was abrogated with zanamivir, a specific flu NA inhibitor [4].
• OBJECTIVE: To examine which clinical signs and symptoms are most predictive of influenza infection in patients with influenza-like illness using a large data set derived from clinical trials of zanamivir [5].

High impact information on zanamivir

• A neuraminidase-inhibition assay and sequencing of the neuraminidase and hemagglutinin genes revealed no zanamivir-resistant variants [6].
• A total of 417 adults with influenza-like illness of < or =48 hours' duration were randomly assigned to one of three treatments: 6.4 mg of zanamivir by intranasal spray plus 10 mg by inhalation, 10 mg of zanamivir by inhalation plus placebo spray, or placebo by both routes [1].
• Viral titers of nasal washings in the group given inhaled and intranasal zanamivir were significantly lower than those in the placebo group [1].
• Recombinant viruses possessing the 1918 NA or both the 1918 HA and 1918 NA were inhibited effectively in both tissue culture and mice by the NA inhibitors, zanamivir and oseltamivir [7].
• We conducted two studies to assess the pharmacokinetics and protective efficacy of a reduced frequency dosing regimen of topical zanamivir [3].

Chemical compound and disease context of zanamivir

• The influenza virus neuraminidase (NA)-specific inhibitor zanamivir (4-guanidino-Neu5Ac2en) is effective in humans when administered topically within the respiratory tract [8].
• 4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid (4-GU-DANA; zanamivir), a sialic acid transition-state analog designed to fit the influenza virus neuraminidase catalytic site, possesses antiviral activity at nanomolar concentrations in vitro [9].
• A single amino acid alteration in the human parainfluenza virus type 3 hemagglutinin-neuraminidase glycoprotein confers resistance to the inhibitory effects of zanamivir on receptor binding and neuraminidase activity [9].
• Comparison of efficacies of RWJ-270201, zanamivir, and oseltamivir against H5N1, H9N2, and other avian influenza viruses [10].
• Mechanism by which mutations at his274 alter sensitivity of influenza a virus n1 neuraminidase to oseltamivir carboxylate and zanamivir [11].

Biological context of zanamivir

• Among the 43 subjects evaluated, decreases in viral shedding occurred in the group receiving one dose of zanamivir 4 h prior to inoculation, whereas no significant benefit was observed in those receiving a single dose 48 h prior to challenge [3].
• In addition, phagocytosis of cells infected with the wild-type virus was severely inhibited when the cells had been maintained in the presence of the NA inhibitor zanamivir [12].
• METHODS: Clinical diagnosis, viral isolation, hemagglutinin inhibition serology, and multiplex, reverse transcription polymerase chain reaction were used to diagnose influenza in patients enrolled in international phase 3 studies designed to investigate the efficacy and safety of an anti-influenza drug (inhaled zanamivir) [13].
• The anti-influenza virus agent 4-GU-DANA (zanamivir) inhibits cell fusion mediated by human parainfluenza virus and influenza virus HA [14].
• The absolute oral bioavailability of zanamivir was low, averaging 2% [15].

Anatomical context of zanamivir

• F activation was assessed by quantitating the irreversible binding of target erythrocytes (RBC) to HN/F-coexpressing cells in the presence of 4-GU-DANA (zanamivir) to release target cells bound only by HN-receptor interactions; the remaining, irreversibly bound target cells are retained via the fusion protein [16].
• This study demonstrates that intravenously administered zanamivir is distributed to the respiratory mucosa and is protective against infection and illness following experimental human influenza A virus inoculation [17].
• In a single-center, randomized study, zanamivir (Relenza) concentrations in induced sputum samples and nasal washings of healthy adults following oral inhalation were measured [18].
• The ability of zanamivir to inhibit the metabolism of CYP probe substrates was studied in human liver microsomes [19].
• On the accumulation of the HA and NA proteins in the trans-Golgi network of MDCK cells by means of low-temperature treatment, desialidation of the HA protein in the presence of Zanamivir was detected by two-dimensional gel electrophoresis [20].

Associations of zanamivir with other chemical compounds

• Compared with amantadine, zanamivir costs $198 per illness day avoided or $185 per quality-adjusted day gained, whereas oseltamivir costs $252 per illness day avoided or $235 per quality-adjusted day gained [21].
• These variants exhibited a 10-fold reduction in susceptibility to GS 4071 and zanamivir (GG167) in an in vitro plaque reduction assay [22].
• A zanamivir-resistant variant bearing a Glu119-to-Gly (Glu119-->Gly) or Glu119-->Ala substitution in an NA (N2) remained susceptible to RWJ-270201 and oseltamivir carboxylate [23].
• Oseltamivir, rimantadine and amantadine are administered by mouth, while zanamivir is administered by oral inhalation in a lactose powder [24].
• Comparison experiments run versus the influenza A (H1N1) virus-induced infection using GS4104, GS4071 and the neuraminidase inhibitor zanamivir (GG167, 4-guanidino-Neu5Ac2en), all administered p.o., indicated a 10-fold or greater potency for inhibiting the infection by GS4104 [25].

Gene context of zanamivir

• Treatment with zanamivir prevented the infection and abrogated the local cytokine and chemokine responses [26].
• Both compounds also considerably decreased NO generation in the IFN-gamma-stimulated macrophages, and zanamivir in the influenza-infected cells as well [27].
• Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. GG167 Influenza Study Group [1].
• We report here that for Newcastle disease virus, the HN receptor avidity is increased by zanamivir, due to activation of a second site that has higher receptor avidity [28].
• In contrast, the enzymatic activities of WSN/Unstable-NAs, the replication of which had no effect on pretreatment with zanamivir, were undetectable in cells under the same conditions [29].

Analytical, diagnostic and therapeutic context of zanamivir

• Zanamivir for the treatment of influenza A and B infection in high-risk patients: a pooled analysis of randomized controlled trials [30].
• METHODS: Meta-analysis of 7 randomized, double-blind, placebo-controlled trials; 3815 mainly healthy adolescents and adults (mean age, 34 years) with an influenzalike illness of less than 2 days' duration were randomly assigned to receive combined inhaled and intranasal zanamivir, inhaled zanamivir, or corresponding placebos [31].
• Zanamivir should have the potential to provide protection during the 2- to 4-week period before full immunity is induced, following vaccination at a time when influenza is circulating in the community [32].
• Chemoprophylaxis of influenza A virus infections, with single doses of zanamivir, demonstrates that zanamivir is cleared slowly from the respiratory tract [33].
• Zanamivir shows potential for prophylaxis in persons for whom vaccination is contraindicated or ineffective, in elderly or high-risk patients in long-term care facilities and in households [34].

References