Zanamivir

Last updated

Zanamivir
Zanamivir structure.svg
Clinical data
Pronunciation /zəˈnæmɪvɪər/
Trade names Relenza
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • AU:B1
Routes of
administration 		Inhalation, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 2% (oral)
Protein binding <10%
Metabolism Negligible
Elimination half-life 2.5–5.1 hours
Excretion Kidney
Identifiers
  • (2R,3R,4S)-4-guanidino-3-(prop-1-en-2-ylamino)-2-((1R,2R)-1,2,3-trihydroxypropyl)-3,4-dihydro-2H-pyran-6-carboxylic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.218.632 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C12H20N4O7
Molar mass 332.313 g·mol−1
3D model (JSmol)
  • O=C(O)C=1O[C@@H]([C@H](O)[C@H](O)CO)[C@H](NC(=O)C)[C@@H](/N=C(\N)N)C=1
  • 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 Yes check.svgY
  • Key:ARAIBEBZBOPLMB-UFGQHTETSA-N Yes check.svgY
   (verify)

Zanamivir is a medication used to treat and prevent influenza caused by influenza A and influenza B viruses. It is a neuraminidase inhibitor and was developed by the Australian biotech firm Biota Holdings. It was licensed to Glaxo in 1990 and approved in the US in 1999, only for use as a treatment for influenza. In 2006, it was approved for prevention of influenza A and B. [3] Zanamivir was the first neuraminidase inhibitor commercially developed. It is marketed by GlaxoSmithKline under the trade name Relenza as a powder for oral inhalation.

Contents

Properties

Zanamivir room temperature solubility in water is 36 mg/mL, in DMSO is 66 mg/mL. [4] It's insoluble in ethanol. [4]

Medical uses

Zanamivir is used for the treatment of infections caused by influenza A and influenza B viruses, but in otherwise-healthy individuals, benefits overall appear to be small. It decreases the risk of one's getting symptomatic, but not asymptomatic influenza. The combination of diagnostic uncertainty, the risk for virus strain resistance, possible side effects and financial cost outweigh the small benefits of zanamivir for the prophylaxis and treatment of healthy individuals. [5]

Since then, genes expressing resistance to zanamivir were found in Chinese people infected with avian influenza A H7N9 during treatment with zanamivir. [6]

Treatment

In otherwise-healthy individuals, benefits overall appear to be small. [5] Zanamivir shortens the duration of symptoms of influenza-like illness (unconfirmed influenza or 'the flu') by less than a day. In children with asthma there was no clear effect on the time to first alleviation of symptoms. [7] Whether it affects the risk of one's need to be hospitalized or the risk of death is not clear. [5] There is no proof that zanamivir reduced hospitalizations or pneumonia and other complications of influenza, such as bronchitis, middle ear infection, and sinusitis. [7] Zanamivir did not reduce the risk of self reported investigator mediated pneumonia or radiologically confirmed pneumonia in adults. The effect on pneumonia in children was also not significant. [8]

Prevention

Low to moderate evidence indicates it decreases the risk of one's getting influenza by 1 to 12% in those exposed. [5] Prophylaxis trials showed that zanamivir reduced the risk of symptomatic influenza in individuals and households, but there was no evidence of an effect on asymptomatic influenza or on other, influenza-like illnesses. Also there was no evidence of reduction of risk of person-to-person spread of the influenza virus. [7] The evidence for a benefit in preventing influenza is weak in children, with concerns of publication bias in the literature. [9]

Resistance

As of 2009, no influenza had shown any signs of resistance in the US. [10] A meta-analysis from 2011 found that zanamivir resistance had been rarely reported. [11] Antiviral resistance can emerge during or after treatment with antivirals in certain people (e.g., immunosuppressed). [12] In 2013 genes expressing resistance to zanamivir (and oseltamivir) were found in Chinese patients infected with avian influenza A H7N9. [6]

Adverse effects

Dosing is limited to the inhalation route. This restricts its usage, as treating asthmatics could induce bronchospasms. [13] In 2006 the Food and Drug Administration (FDA) found that breathing problems (bronchospasm), including deaths, were reported in some patients after the initial approval of Relenza. Most of these patients had asthma or chronic obstructive pulmonary disease. Relenza therefore was not recommended for treatment or prophylaxis of seasonal influenza in individuals with asthma or chronic obstructive pulmonary disease. [14] In 2009 the zanamivir package insert contains precautionary information regarding risk of bronchospasm in patients with respiratory disease. [15] GlaxoSmithKline (GSK) and FDA notified healthcare professionals of a report of the death of a patient with influenza having received zanamivir inhalation powder, which was solubilized and administered by mechanical ventilation. [16]

In adults there was no increased risk of reported adverse events in trials. There was little evidence of the possible harms associated with the treatment of children with zanamivir. [7] Zanamivir has not been known to cause toxic effects and has low systemic exposure to the human body. [17]

Mechanism of action

Zanamivir works by binding to the active site of the neuraminidase protein, rendering the influenza virus unable to escape its host cell and infect others. [18] It is also an inhibitor of influenza virus replication in vitro and in vivo. In clinical trials, zanamivir was found to reduce the time-to-symptom resolution by 1.5 days if therapy was started within 48 hours of the onset of symptoms.[ citation needed ]

The bioavailability of zanamivir is 2%. After inhalation, zanamivir is concentrated in the lungs and oropharynx, where up to 15% of the dose is absorbed and excreted in urine. [19]

History

Zanamivir was first made in 1989 by scientists led by Peter Colman [20] [21] and Joseph Varghese [22] at the Australian CSIRO, in collaboration with the Victorian College of Pharmacy, and the Monash University. Zanamivir was the first of the neuraminidase inhibitors. The discovery was initially funded by the Australian biotechnology company Biota and was part of Biota's ongoing program to develop antiviral agents through rational drug design. Its strategy relied on the availability of the structure of influenza neuraminidase by X-ray crystallography. It was also known, as far back as 1974, that 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA), a sialic acid analogue, is an inhibitor of neuraminidase. [23]

Computational chemistry techniques were used to probe the active site of the enzyme, in an attempt to design derivatives of DANA that would bind tightly to the amino acid residues of the catalytic site, so would be potent and specific inhibitors of the enzyme. The GRID software by Molecular Discovery was used to determine energetically favourable interactions between various functional groups and residues in the catalytic site canyon. This investigation showed a negatively charged zone occurs in the neuraminidase active site that aligns with the C4 hydroxyl group of DANA. This hydroxyl is, therefore, replaced with a positively charged amino group; the 4-amino DANA was shown to be 100 times better as an inhibitor than DANA, owing to the formation of a salt bridge with a conserved glutamic acid (119) in the active site. Glu 119 was also noticed to be at the bottom of a conserved pocket in the active site that is just big enough to accommodate the larger, but more basic guanidine functional group. [24] Zanamivir, a transition-state analogue inhibitor of neuraminidase, was the result. [25]

In 1999, the product was approved for marketing in the US and Europe for treatment of influenza A and B. The FDA advisory committee had recommended by a vote 13 to 4 that it should not be approved, because it lacked efficacy and was no more effective than placebo when the patients were on other drugs such as paracetamol. But the FDA leadership overruled the committee and criticised its reviewer, biostatistician Michael Elashoff. The review of oseltamivir, which was also in approval process at that time, was taken away from him, and reassigned to someone else. [26] In 2006 zanamivir was approved in the US and Europe for prevention of influenza A and B. [3]

Related Research Articles

<span class="mw-page-title-main">Antiviral drug</span> Medication used to treat a viral infection

Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Antiviral drugs are a class of antimicrobials, a larger group which also includes antibiotic, antifungal and antiparasitic drugs, or antiviral drugs based on monoclonal antibodies. Most antivirals are considered relatively harmless to the host, and therefore can be used to treat infections. They should be distinguished from virucides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Natural virucides are produced by some plants such as eucalyptus and Australian tea trees.

<span class="mw-page-title-main">Oseltamivir</span> Antiviral medication used against influenza A and influenza B

Oseltamivir, sold under the brand name Tamiflu, is an antiviral medication used to treat and prevent influenza A and influenza B, viruses that cause the flu. Many medical organizations recommend it in people who have complications or are at high risk of complications within 48 hours of first symptoms of infection. They recommend it to prevent infection in those at high risk, but not the general population. The Centers for Disease Control and Prevention (CDC) recommends that clinicians use their discretion to treat those at lower risk who present within 48 hours of first symptoms of infection. It is taken by mouth, either as a pill or liquid.

<span class="mw-page-title-main">Rimantadine</span> Drug used to treat influenzavirus A infection

Rimantadine is an orally administered antiviral drug used to treat, and in rare cases prevent, influenzavirus A infection. When taken within one to two days of developing symptoms, rimantadine can shorten the duration and moderate the severity of influenza. Rimantadine can mitigate symptoms, including fever. Both rimantadine and the similar drug amantadine are derivates of adamantane. Rimantadine is found to be more effective than amantadine because when used the patient displays fewer symptoms. Rimantadine was approved by the Food and Drug Administration (FDA) in 1994.

<span class="mw-page-title-main">Amantadine</span> Medication used to treat dyskinesia

Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended because of widespread drug resistance. It acts as a nicotinic antagonist, dopamine agonist, and noncompetitive NMDA antagonist. The antiviral mechanism of action is antagonism of the influenzavirus A M2 proton channel, which prevents endosomal escape.

<span class="mw-page-title-main">Neuraminidase</span> Glycoside hydrolase enzymes that cleave the glycosidic linkages of neuraminic acids

Exo-α-sialidase is a glycoside hydrolase that cleaves the glycosidic linkages of neuraminic acids:

Neuraminidase inhibitors (NAIs) are a class of drugs which block the neuraminidase enzyme. They are a commonly used antiviral drug type against influenza. Viral neuraminidases are essential for influenza reproduction, facilitating viral budding from the host cell. Oseltamivir (Tamiflu), zanamivir (Relenza), laninamivir (Inavir), and peramivir belong to this class. Unlike the M2 inhibitors, which work only against the influenza A virus, NAIs act against both influenza A and influenza B.

<span class="mw-page-title-main">Influenza A virus subtype H1N1</span> Subtype of Influenza A virus

In virology, influenza A virus subtype H1N1 (A/H1N1) is a subtype of influenza A virus. Major outbreaks of H1N1 strains in humans include the 1918 Spanish flu pandemic, the 1977 Russian flu pandemic and the 2009 swine flu pandemic. It is an orthomyxovirus that contains the glycoproteins hemagglutinin (H) and neuraminidase (N), antigens whose subtypes are used to classify the strains of the virus as H1N1, H1N2 etc. Hemagglutinin causes red blood cells to clump together and binds the virus to the infected cell. Neuraminidase is a type of glycoside hydrolase enzyme which helps to move the virus particles through the infected cell and assist in budding from the host cells.

<span class="mw-page-title-main">Peramivir</span> Antiviral drug targeting influenza

Peramivir is an antiviral drug developed by BioCryst Pharmaceuticals for the treatment of influenza. Peramivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells. It is approved for intravenous administration.

<span class="mw-page-title-main">Influenza treatment</span> Therapy and pharmacy for the common infectious disease

Treatments for influenza include a range of medications and therapies that are used in response to disease influenza. Treatments may either directly target the influenza virus itself; or instead they may just offer relief to symptoms of the disease, while the body's own immune system works to recover from infection.

<span class="mw-page-title-main">Umifenovir</span> Chemical compound

Umifenovir, sold under the brand name Arbidol, is an antiviral medication for the treatment of influenza and COVID infections used in Russia and China. The drug is manufactured by Pharmstandard. It is not approved by the U.S. Food and Drug Administration (FDA) for the treatment or prevention of influenza.

<span class="mw-page-title-main">Nitazoxanide</span> Broad-spectrum antiparasitic and antiviral medication

Nitazoxanide, sold under the brand name Alinia among others, is a broad-spectrum antiparasitic and broad-spectrum antiviral medication that is used in medicine for the treatment of various helminthic, protozoal, and viral infections. It is indicated for the treatment of infection by Cryptosporidium parvum and Giardia lamblia in immunocompetent individuals and has been repurposed for the treatment of influenza. Nitazoxanide has also been shown to have in vitro antiparasitic activity and clinical treatment efficacy for infections caused by other protozoa and helminths; evidence as of 2014 suggested that it possesses efficacy in treating a number of viral infections as well.

<span class="mw-page-title-main">Influenza</span> Infectious disease

Influenza, commonly known as "the flu" or just "flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms begin from one to four days after exposure to the virus and last for about 2–8 days. Diarrhea and vomiting can occur, particularly in children. Influenza may progress to pneumonia, which can be caused by the virus or by a subsequent bacterial infection. Other complications of infection include acute respiratory distress syndrome, meningitis, encephalitis, and worsening of pre-existing health problems such as asthma and cardiovascular disease.

<span class="mw-page-title-main">Viral neuraminidase</span> InterPro Family

Viral neuraminidase is a type of neuraminidase found on the surface of influenza viruses that enables the virus to be released from the host cell. Neuraminidases are enzymes that cleave sialic acid groups from glycoproteins. Viral neuraminidase was discovered by Alfred Gottschalk at the Walter and Eliza Hall Institute in 1957. Neuraminidase inhibitors are antiviral agents that inhibit influenza viral neuraminidase activity and are of major importance in the control of influenza.

<span class="mw-page-title-main">2009 swine flu pandemic</span> 2009–2010 pandemic of swine influenza caused by H1N1 influenza virus

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<span class="mw-page-title-main">Laninamivir</span> Chemical compound

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Margaret Tisdale was a Welsh-born clinical virologist known for her studies of antiviral resistance in HIV and influenza virus, and for coordinating the development of the anti-influenza drug zanamivir.

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References

  1. ↑ "Relenza- zanamivir powder". DailyMed. 19 October 2021. Retrieved 30 September 2022.
  2. ↑ "List of nationally authorised medicinal products" (PDF). European Medicines Agency.
  3. 1 2 "FDA Approves a Second Drug for the Prevention of Influenza A and B in Adults and Children FDA press release March 29, 2006". FDA. Archived from the original on 6 March 2010. Retrieved 16 December 2019.
  4. 1 2 Zanamivir, 2023
  5. 1 2 3 4 Michiels B, Van Puyenbroeck K, Verhoeven V, Vermeire E, Coenen S (2013). "The value of neuraminidase inhibitors for the prevention and treatment of seasonal influenza: a systematic review of systematic reviews". PLOS ONE. 8 (4): e60348. Bibcode:2013PLoSO...860348M. doi: 10.1371/journal.pone.0060348 . PMC   3614893 . PMID   23565231.
  6. 1 2 Hu Y, Lu S, Song Z, Wang W, Hao P, Li J, et al. (June 2013). "Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance". Lancet. 381 (9885): 2273–2279. doi:10.1016/S0140-6736(13)61125-3. PMID   23726392. S2CID   7537862.
  7. 1 2 3 4 Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, et al. (April 2014). "Neuraminidase inhibitors for preventing and treating influenza in adults and children". The Cochrane Database of Systematic Reviews. 2014 (4): CD008965. doi:10.1002/14651858.CD008965.pub4. PMC   6464969 . PMID   24718923.
  8. ↑ Heneghan CJ, Onakpoya I, Thompson M, Spencer EA, Jones M, Jefferson T (April 2014). "Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments". BMJ. 348 (apr09 2): g2547. doi:10.1136/bmj.g2547. PMC   3981976 . PMID   24811412.
  9. ↑ Wang K, Shun-Shin M, Gill P, Perera R, Harnden A (April 2012). "Neuraminidase inhibitors for preventing and treating influenza in children (published trials only)". The Cochrane Database of Systematic Reviews. 2012 (4): CD002744. doi:10.1002/14651858.CD002744.pub4. PMC   6599832 . PMID   22513907.
  10. ↑ "2008-2009 Influenza Season Week 32 ending August 15, 2009". Flu Activity & Surveillance. Centers for Disease Control and Prevention (CDC). 21 August 2009.
  11. ↑ Thorlund K, Awad T, Boivin G, Thabane L (May 2011). "Systematic review of influenza resistance to the neuraminidase inhibitors". BMC Infectious Diseases. 11 (1): 134. doi: 10.1186/1471-2334-11-134 . PMC   3123567 . PMID   21592407.
  12. ↑ "Influenza Antiviral Medications: Summary for Clinicians". CDC. 11 May 2018. Retrieved 21 April 2014.
  13. ↑ Hayden FG (December 2001). "Perspectives on antiviral use during pandemic influenza". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 356 (1416): 1877–1884. doi:10.1098/rstb.2001.1007. PMC   1088564 . PMID   11779387.
  14. ↑ "FDA Approves a Second Drug for the Prevention of Influenza A and B in Adults and Children". FDA press release.
  15. ↑ "Safe and Appropriate Use of Influenza Drugs". Public Health Advisories (Drugs). U.S. Food and Drug Administration (FDA). 30 April 2009. Archived from the original on 4 November 2009. Retrieved 11 November 2009.
  16. ↑ "Relenza (zanamivir) Inhalation Powder". Food and Drug Administration . Archived from the original on 12 October 2009.
  17. ↑ Freund B, Gravenstein S, Elliott M, Miller I (October 1999). "Zanamivir: a review of clinical safety". Drug Safety. 21 (4): 267–281. doi:10.2165/00002018-199921040-00003. PMID   10514019. S2CID   25945928.
  18. ↑ Cyranoski D (September 2005). "Threat of pandemic brings flu drug back to life". Nature Medicine. 11 (9): 909. doi: 10.1038/nm0905-909 . PMID   16145557.
  19. ↑ Moscona A (September 2005). "Neuraminidase inhibitors for influenza". The New England Journal of Medicine. 353 (13): 1363–1373. doi: 10.1056/NEJMra050740 . PMID   16192481. S2CID   17162678.
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  21. ↑ "Colman, Peter Malcolm - CSIROpedia". Archived from the original on 4 October 2013. Retrieved 2 October 2013.
  22. ↑ "Varghese, Joseph Noozhumurry - CSIROpedia". Archived from the original on 5 October 2013. Retrieved 2 October 2013.
  23. ↑ Meindl P, Bodo G, Palese P, Schulman J, Tuppy H (April 1974). "Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid". Virology. 58 (2): 457–463. doi:10.1016/0042-6822(74)90080-4. PMID   4362431.
  24. ↑ Laver G (1 March 2007). "Flu drugs - pathway to discovery". Education in Chemistry . Vol. 44, no. 2. Royal Society of Chemistry. pp. 48–52. ISSN   0013-1350 . Retrieved 19 June 2018.
  25. ↑ von Itzstein M, Wu WY, Kok GB, Pegg MS, Dyason JC, Jin B, et al. (June 1993). "Rational design of potent sialidase-based inhibitors of influenza virus replication". Nature. 363 (6428): 418–423. Bibcode:1993Natur.363..418V. doi:10.1038/363418a0. PMID   8502295. S2CID   4359333.
  26. ↑ Cohen D, Carter P (June 2010). "Conflicts of interest. WHO and the pandemic flu "conspiracies"". BMJ. 340 (jun03 4): c2912. doi:10.1136/bmj.c2912. PMID   20525679. S2CID   35959611.
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