Influenza A(IC50= 0.95 nM);Influenza B(IC50= 2.7 nM)

Zanamivir (GR-121167X; GG-167; Relenza) interacts with a group of amino acids in the active site of neuraminidase, which are conserved in all influenza A and B strains.By inhibiting neuraminidase's ability to cleave sialic acid on cell receptors, zanamivir stops the release and dissemination of newly formed virions[2].

Zanamivir has a poor bioavailability in oral administration, with only 4–17% of the agent. Because of its strong hydrophilic nature, which restricts its transport across the intestinal epithelium, oral delivery of zanamivir has proven to be problematic. When combined with zanamivir, permeability enhancers like sodium cholate and hydroxypropyl β-cyclodextrin can improve intestinal permeability[3].

Rats
Combinations Rats kept conscious are given IV-R (reference Zanamivir saline solution for intravenous injection) at a dose of 1 mg/kg.PO-SC (Zanamivir with SC for p.o.) and PO-C (Zanamivir control solution for p.o.) are given oral Zanamivir doses of 10 mg/kg. Before, at 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after administration, blood samples are taken. Three rats from each group are sacrificed at each sampling point to remove the lungs following blood collection.After the rats' lungs are removed through a chest incision, the lungs are cleaned with saline. After that, the lungs are placed in an E-tube and kept in a freezer at -80°C until they are examined. After being centrifuged at 1,500 × g for 10 minutes, plasma samples are collected and kept at -20°C until analysis. Zanamivir is analyzed using the previously stated LC-MS/MS method in both plasma and lungs[3].

Absorption, Distribution and Excretion
The absolute bioavailability after oral administration is very low (2%). Bioavailability after oral inhalation is 4% to 17%. The drug is excreted unchanged in the urine and is completely eliminated within 24 hours of a single dose. Unabsorbed drug is excreted in the feces. Zanamivir is excreted unchanged via the kidneys. 2.5 - 10.9 L/h [after oral inhalation of 10 mg] 5.3 L/h [after a single intravenous injection of 4 mg or 2 mg in patients with normal renal function] 2.7 L/h [after a single intravenous injection of 4 mg or 2 mg in patients with mild to moderate renal impairment] 0.8 L/h [after a single intravenous injection of 4 mg or 2 mg in patients with severe renal impairment] Protein binding: Very low (<10%).
Oral inhalation of zanamivir results in systemic absorption, with an absorption rate of approximately 4% to 17%.
Elimination: Renal: Excreted unchanged in the urine, with a single dose eliminated within 24 hours. Total clearance ranges from 2.5 to 10.9 L/h. Fecal: Unabsorbed drug is excreted in the feces.
Time to Peak Effect: 72 hours.
For more complete data on the absorption, distribution, and excretion of zanamivir (7 metabolites), please visit the HSDB record page.

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Metabolism/Metabolites
Unmetabolized
Unmetabolized.

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Biological Half-Life
2.5–5.1 hours
The serum half-life of zanamivir after oral inhalation administration is 2.5 to 5.1 hours.

Hepatotoxicity
In randomized controlled trials, 2% to 3% of patients receiving zanamivir experienced elevated ALT or AST levels more than twice the upper limit of normal, but the incidence was similar in the placebo group. Despite the widespread use of zanamivir, there is little evidence that inhaled zanamivir causes liver injury, whether asymptomatic elevations in serum enzymes or clinically apparent liver disease. In a preliminary study of intravenous zanamivir for severe influenza, approximately 10% of patients reported elevated serum enzymes, occasionally accompanied by jaundice, but the relationship between zanamivir and potentially severe viral infection remains unclear. Probability score: E (unlikely a cause of clinically apparent liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information regarding the use of zanamivir during lactation. One group of authors estimated that if the mother inhaled a 10 mg dose of the drug, a fully breastfed 5 kg infant would receive approximately 0.075 mg of the drug daily from breast milk, less than 1% of the dose for older children. Furthermore, due to poor oral absorption of zanamivir, it is unlikely to reach clinically significant infant blood concentrations.
◉ Effects on breastfed infants
No relevant published information found as of the revision date.
◉ Effects on lactation and breast milk
No relevant published information found as of the revision date.

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Protein binding
Zanamivir has limited plasma protein binding (<10%).

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Interactions
Zanamivir is not a substrate of, nor does it affect, cytochrome P450 (CYP) isoenzymes (CYP1A1/2, 2A6, 2C9, 2C18, 2D6, 2E1, and 3A4) in human liver microsomes.

[1]. Comparison of the activities of zanamivir, oseltamivir, and RWJ-270201 against clinical isolates ofinfluenza virus and neuraminidase inhibitor-resistant variants. Antimicrob Agents Chemother. 2001 Dec;45(12):3403-8.

[2]. Management of influenza virus infections with neuraminidase inhibitors: detection, incidence, and implications of drug resistance. Treat Respir Med. 2005;4(2):107-16.

[3]. Zanamivir oral delivery: enhanced plasma and lung bioavailability in rats. Biomol Ther (Seoul). 2013 Mar;21(2):161-9.

Zanamivir belongs to the guanidine class of compounds. It is an EC 3.2.1.18 (exo-α-sialidase) inhibitor and also an antiviral drug. It is a guanidino-neuraminidide that inhibits neuraminidase. Zanamivir is a neuraminidase inhibitor. Its mechanism of action is as a neuraminidase inhibitor. Zanamivir is an inhibitor of influenza virus neuraminidase and is administered via inhalation for the treatment and prevention of influenza A and B. At least in the case of inhalation administration, zanamivir has not been found to be associated with clinically significant liver injury. Zanamivir is a sialic acid analog neuraminidase inhibitor with antiviral activity. When administered via aerosol inhalation, zanamivir selectively binds to and inhibits the cleavage of sialic acid residues on the host cell membrane-binding glycoprotein receptor mediated by influenza A and B virus neuraminidase, thereby preventing the release of progeny viruses from the host cell surface and inhibiting further viral replication. A guanidino-neuraminidide that inhibits neuraminidase. Indications For the prevention and treatment of influenza A and B. FDA Label Dectova is indicated for the treatment of complicated and potentially life-threatening influenza A or B virus infections in adults and children (≥6 months) when: the patient's influenza virus is known or suspected to be resistant to other antiviral drugs besides zanamivir, and/or other antiviral drugs. Drugs used to treat influenza, including inhaled zanamivir, are not suitable for this patient. Dectova should be used according to official guidelines. Prevention and Treatment of Influenza Mechanism of Action Zanamivir's mechanism of action is by inhibiting influenza virus neuraminidase, which may alter the aggregation and release of viral particles. By binding to and inhibiting the neuraminidase protein, the drug prevents the influenza virus from escaping host cells and infecting other cells. Zanamivir is a potent, selective, competitive inhibitor of influenza virus neuraminidase, an enzyme essential for viral replication. Neuraminidase can cleave terminal sialic acid residues from glycoconjugates, thereby releasing the virus from infected cells, preventing the formation of viral aggregates after release from host cells, and potentially reducing the inactivation effect of respiratory mucus on the virus. Zanamivir is a selective inhibitor of neuraminidase in influenza A and B viruses, potentially altering viral particle aggregation and release.
Therapeutic Uses
Antiviral drug; enzyme inhibitor
Currently, the U.S. Centers for Disease Control and Prevention (CDC) recommends the use of oseltamivir or zanamivir for the treatment of swine influenza (H1N1) virus infection.
Drug: Antiviral drug; influenza virus neuraminidase inhibitor
Zanamivir is indicated for the treatment of uncomplicated acute illness caused by influenza A virus in adults and children aged 7 years and older, with symptoms present for no more than 2 days. Zanamivir must be started within 48 hours of the onset of flu symptoms. /U.S. product label contains/
For more complete data on the therapeutic uses of zanamivir (6 types), please visit the HSDB record page.

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Drug Warning
The swine flu (H1N1) virus contains a unique combination of gene segments that have not been previously reported in swine or human influenza viruses in the United States or elsewhere. The H1N1 virus is resistant to amantadine and ribavirin, but oseltamivir or zanamivir.
Some patients taking Relenza have reported bronchospasm and decreased lung function. Many (but not all) of these patients have underlying airway diseases such as asthma or chronic obstructive pulmonary disease. Due to the risk of serious adverse events and the lack of proven efficacy in this population, zanamivir is generally not recommended for the treatment of patients with underlying airway diseases. Some patients who experienced serious adverse events during zanamivir treatment have ultimately died, but causality is difficult to assess. Any patient experiencing bronchospasm or decreased respiratory function should discontinue zanamivir; immediate treatment and hospitalization may be required. Some patients without a history of lung disease may also experience respiratory abnormalities due to acute respiratory infections. These abnormalities may resemble adverse drug reactions or increase the patient's risk of developing adverse drug reactions. FDA Pregnancy Risk Category: B / No evidence of risk to humans. Although adverse reactions have been found in animal studies, adequately controlled studies in pregnant women have not shown an increased risk of fetal malformations; or, in the absence of adequate human studies, animal studies have shown no fetal risk. The possibility of fetal harm is small, but it still exists. / In 1–3% or more of adults and children 12 years and older, adverse reactions include diarrhea, nausea, vomiting, nasal symptoms, bronchitis, sinusitis, cough, ear, nose, and throat infections, headache, and dizziness. The incidence of no adverse reactions exceeds 3%. In children aged 5–12 years, the incidence of adverse reactions is up to 5%, including ear, nose, and throat infections, vomiting, nausea, and diarrhea. Some adverse reactions may be due to inhalation of lactose carriers. Bronchospasm and anaphylactoid reactions (including oropharyngeal edema and severe rash) have been reported. Unlike amantadine and ribavirin, neuraminidase inhibitors such as zanamivir do not appear to have adverse effects on the central nervous system. For more complete data on drug warnings for zanamivir (10 in total), please visit the HSDB record page.

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Pharmacodynamics
Zanamivir is an antiviral drug belonging to the neuraminidase inhibitor class, indicated for the treatment of uncomplicated acute illness caused by influenza A and B viruses in adults and children aged 7 years and older, with symptoms lasting no more than 2 days. Studies have shown that zanamivir also significantly inhibits human sialidases NEU3 and NEU2 at inhibitory concentrations in the micromolar range (Ki values of 3.7 ± 0.48 and 12.9 ± 0.07 μmol, respectively), which may be the cause of some rare side effects of zanamivir.

C12H20N4O7

332.313

332.133

C, 43.37; H, 6.07; N, 16.86; O, 33.70

139110-80-8

Zanamivir (hydrate)(5:1);171094-50-1

60855

White to off-white solid powder

1.8±0.1 g/cm3

256ºC (dec.)

1.679

-4.13

7

8

6

23

518

5

O1C(C(=O)O[H])=C([H])[C@@]([H])([C@]([H])([C@]1([H])[C@@]([H])([C@@]([H])(C([H])([H])O[H])O[H])O[H])N([H])C(C([H])([H])[H])=O)/N=C(\N([H])[H])/N([H])[H]

ARAIBEBZBOPLMB-UFGQHTETSA-N

InChI=1S/C12H20N4O7/c1-4(18)15-8-5(16-12(13)14)2-7(11(21)22)23-10(8)9(20)6(19)3-17/h2,5-6,8-10,17,19-20H,3H2,1H3,(H,15,18)(H,21,22)(H4,13,14,16)/t5-,6+,8+,9+,10+/m0/s1

(2R,3R,4S)-3-acetamido-4-(diaminomethylideneamino)-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid

Zanamivir; GR-121167X; GG167; GR121167X; GG-167; GR 121167X; GG 167; trade name Relenza.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : 33.33~36 mg/mL (~100.30 mM)
DMSO : ~66 mg/mL ( ~198.6 mM)

Solubility in Formulation 1: 9.09 mg/mL (27.35 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)