Zanamivir

Sample preparation Condition a 1 mL 50 mg isolute SCX SPE cartridge with 500 aL MeOH and 500 xL 10% acetic acid water. Vortex 200 (xL serum with 100 xL 5 IS in water, 500 LL MeCN, and 100 jxL 3% acetic acid in water, let stand at room temperature for 5 min, centrifuge at 1400 g for 10 min, add the supernatant to the SPE cartridge, elute with two 500 m-L portions of 10% triethylamine in MeOHwater 50 50. Evaporate the eluate to dryness under a stream of nitrogen at 60°, reconstitute the residue with 200 iL mobile phase, vortex for 10 s, centrifuge at 5000 g for 5 min, inject a 20-200 lL aliquot. 

Mobile phase MeCN water acetic acid 50 50 1 

Detector MS, PE Sciex API 300 triple quadrupole, TurboIonSpray, positive ion mode, 20% of column effluent entered the detector, collision gas nitrogen, coUision energy 28 eV, m/z 333-60 

Brookes, S.T. Barrow, A. Dunn, J.A. Grosse, C.M. Liquid chromatographic-tandem mass spectrometric method for the determination of the neurtuninidase inhibitor zanamivir (GG167) in human serum, J.Chromatogr.B, 1999, 732, 383-393. 

Mobile phase Gradient. MeCN buffer 20 80 for 12 min, to 80 20 (step gradient), maintain at 80 20 for 5 min, re-equilibrate at initial conditions for 10 min. (Prepare the buffer by adding 100 mL 1 M tris(hydroxymethyl)methylamine (Tris) and 29.4 mL 1 M HCl to water and making up to 2 L with water (50 mM pH 8.5).) 

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The influenza virus inhibitors, zanamivir, and oseltamivir, act outside the cell after virus particles have been formed. The dtugs have been designed to fit into the active site of the viral envelope enzyme neuraminidase, which is required to cleave sialic acid off the surface of the producing cells. When its activity is blocked, new virus particles stay attached to the cell surface through binding of the virus protein hemagglutinin to sialic acid and are prevented from spreading to other cells. 

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... 

Zanamivir is used cautiously with pregnancy (Category C), lactation, asthma, COPD, or other underlying respiratory diseases. No significant drug interactions have been reported with the use of zanamivir. 

ZANAMIVIR This drug is available as a powder blister for inhalation. The usual dose is 2 inhalations (one 5-mg blister per inhalation) administered with a Diskhaler device. The drug should be started within 2 days onset of flu symptoms. The drug is taken every 12 hours. 

ZANAMIVIR There is a risk for bronchospasm in patients with asthma or COPD. A fast-acting bron-chodilator should be on hand in case bronchospasm occurs. Zanamivir use should be discontinued and the primary health care provider notified promptly if respiratory symptoms worsen. 

Zanamivir This drug is taken every 12 hours for... 

A patient is prescribed 2 inhalations of zanamivir. The drug is available as one 5-mg blister per inhalation and is to be given with a Disklialer device. How many milligrams will the nurse administer witii 2 inhalations ... 

Benazepril Docetaxel Fluazacort Imiquimod Irbesartan Midodtine Oseltamivir Paclitaxel Pemirolast Pranlukast Tazanolast Tranylcypromine Zanamivir Zidovudine sodium benzenesultinate... 

C[iH4F,iN20gS2 157875-58-6) see Imiquimod trifluoromethanesulfonic acid triethylsilyl ester (C7Hi5F303SSi 79271-56-0) see Tacrolimus trifluoromethanesulfonic anhydride (C2F(,05S2 358-23-6) see Imiquimod Zanamivir... 

The Discovery of Zanamivir, the First Potent Designer Anti-Influenza Drug.. 119... 

GlaxoWellcome (now GlaxoSmithKline) licensed 4-deoxy-4-guanidino-Neu5Ac2en 12 as a lead drug candidate under the generic name zanamivir and... 

Fig. 5 Key interactions of 4-deoxy-4-guanidino-Neu5Ac2en (zanamivir) 12 with the active site of influenza A virus sialidase [Figure generated from crystal strucmre data (PDB - Innc) using LIGPLOT (Wallace et al. 1995)]. To the right is shown zanamivir 12 in the same orientation...

The discovery of the potent in vitro sialidase inhibitory activity and in vivo efficacy of zanamivir 12, and the increasing availability of 3D structural data for influenza virus sialidases in the 1990s, particularly with Neu5Ac and various inhibitors bound into the active site, provided a platform for further drug discovery efforts targeting... 

Further Developments on the Neu5Ac2en Template Second-Generation Zanamivir... 

A pro-drug approach for improving the pharmacokinetics of zanamivir has recently shown some promise. The alkoxyalkyl ester 23 of zanamivir, with long alkyl chains chosen to counteract the high hydrophUicity of the molecule, was reported to show significant protective effects against influenza (HlNl) infection in mice upon oral or intraperitoneal administration (Liu et al. 2007). 

The C-6 carboxamide analogues of zanamivir, represented by the general structure 24, provided an avenue to introduce more hydrophobic side-chains onto the dihydropyran scaffold to interact with the hydrophobic regions of subsites S4 and S5 (reviewed in Islam and von Itzstein 2007). The most active tertiary amides (24 = alkyl) showed comparable inhibitory activity to their glycerol side-... 

Functionalisation Through the C-7 Position of Zanamivir The Development of Long Acting Sialidase Inhibitors... 

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