Zanamivir

Systematic (IUPAC) name
(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
Clinical data
Trade names	Relenza
AHFS/Drugs.com	monograph
Pregnancy cat.	B1 (Au), C (US)
Legal status	S4 (Au), POM (UK), ℞-only (U.S.)
Routes	Inhalation
Pharmacokinetic data
Bioavailability	2% (oral)
Protein binding	<10%
Metabolism	Negligible
Half-life	2.5–5.1 hours
Excretion	Renal
Identifiers
CAS number	139110-80-8 Y
ATC code	J05AH01
PubChem	CID 60855
DrugBank	DB00558
ChemSpider	54842 Y
UNII	L6O3XI777I Y
KEGG	D00902 Y
ChEBI	CHEBI:50663 Y
ChEMBL	CHEMBL222813 Y
Synonyms	5-acetamido- 4-guanidino- 6-(1,2,3-trihydroxypropyl)- 5,6-dihydro- 4H-pyran- 2-carboxylic acid
Chemical data
Formula	C12H20N4O7
Mol. mass	332.31 g/mol
SMILES	eMolecules & PubChem
InChI 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 Y Key:ARAIBEBZBOPLMB-UFGQHTETSA-N Y
Y (what is this?)  (verify)

Influenza (Flu)
Types
Avian (A/H5N1 subtype) Canine Equine Swine (A/H1N1 subtype)
Vaccines
2009 pandemic (Pandemrix) ACAM-FLU-A Fluzone Influvac Live attenuated (FluMist) Optaflu
Treatment
Amantadine Arbidol Laninamivir Oseltamivir Peramivir Rimantadine Vitamin D Zanamivir
Pandemics
2009 Swine 1968–1969 Hong Kong 1918
Outbreaks
2008 West Bengal 2007 Bernard Matthews H5N1 2007 Australian equine 2006 H5N1 India 1976 swine flu
See also
Flu season Influenza evolution Influenza research Influenza-like illness
v t e

Zanamivir INN ( /zəˈnæmɨvɪər/) is a neuraminidase inhibitor used in the treatment and prophylaxis of influenza caused by influenza A virus and influenza B virus. Zanamivir was the first neuraminidase inhibitor commercially developed. It is currently marketed by GlaxoSmithKline under the trade name Relenza as a powder for oral inhalation.

According to the Centers for Disease Control and Prevention (CDC), no flu, seasonal or pandemic, has shown any signs of resistance to zanamivir.^[1]

History[link]

Zanamivir was discovered in 1989 by scientists led by Mark von Itzstein at the Victorian College of Pharmacy, Monash University, in collaboration with the CSIRO and scientists at Glaxo, UK. 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, was an inhibitor of neuraminidase.^[2] Sialic acid (N-acetyl neuraminic acid, NANA), the substrate of neuraminidase, is itself a mild inhibitor of the enzyme, but the dehydrated derivative DANA, a transition-state analogue, is a better inhibitor.

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, and 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 showed there was a negatively charged zone in the neuraminidase active site that aligned with the C₄ hydroxyl group of DANA. This hydroxyl was therefore replaced with a positively charged amino group; the 4-amino DANA was 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. It was also noticed that Glu 119 was at the bottom of a conserved pocket in the active site just big enough to accommodate a more basic functional positively charged group, such as a guanidino group, which was also larger than the amino group.^[3] Zanamivir, a transition-state analogue inhibitor of neuraminidase, was the result.^[4]

As Biota was a small company, it did not have the resources to bring zanamivir to market by itself. In 1990, zanamivir patent rights were licensed to Glaxo, now GlaxoSmithKline (GSK). In 1999, the product was approved for marketing in the US and subsequently has been registered by GSK in a total of 70 countries (GlaxoSmithKline News release, 2006). Zanamivir is delivered via Glaxo's proprietary Diskhaler inhalation device. The license agreement entitled Biota to receive a 7% royalty on Glaxo's sales of zanamivir.

Developments[link]

Recently, the reported oseltamivir-resistance H5N1 virus neuraminidase still retaining susceptibility to zanamivir indicates that the structure of zanamivir has some advantages over oseltamivir in binding to the active pocket of H5N1 neuraminidase.^[5][6][7]

In January 2011, GlaxoSmithKline started a pivotal study testing intravenous zanamivir against oral oseltamivir (the Tamiflu pill) as a treatment for patients hospitalised with influenza. GSK's press release

As a proven anti-influenza drug target, neuraminidase continues to be attractive for the development of new inhibitors. The crystal structure of H5N1 avian influenza neuraminidase (PDB code: 2HTY) provides the three-dimensional structural information and opportunity for finding new inhibitors in this regard, because the existing inhibitors, such as oseltamivir and zanamivir, were developed based on different structures of neuraminidase, such as subtypes N9, N2, and type B genus of influenza virus.

Pharmacology[link]

Zanamivir is specifically for the treatment of infections caused by Influenzavirus A and Influenzavirus B.

Influenza, commonly known as the flu, is caused by a virus which targets the body's respiratory cells and damages the lining of the respiratory tract, leading to swelling and inflammation of the tract. Influenza spreads rapidly by replicating itself inside the host cell, producing hundreds of copies of the virus in a short period. In approximately an hour the virus can destroy the host cell and propel its replications out into the body to find new host cells. For some people, the flu and its complications can be very serious, even fatal.

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.^[8] It is also an inhibitor of influenza virus replication in vitro and in vivo. In clinical trials it was found that zanamivir was able to reduce the time to symptom resolution by 1.5 days if therapy was started within 48 hours of the onset of symptoms.

Dosing and side effects[link]

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.^[9]

Dosing is limited to the inhaled route. This restricts its usage, as treating asthmatics could induce bronchospasms.^[10] The U.S. Food and Drug Administration (FDA) has issued a Public Health Advisory warning that it has received some reports of respiratory problems following inhalation of zanamivir by patients with underlying asthma or chronic obstructive pulmonary disease. The zanamivir package insert contains precautionary information regarding risk of bronchospasm in patients with respiratory disease.^[11]

Zanamivir has not been known to cause toxic effects, does not spread around through the body's systemic circulation and shows no signs of viral resistance from any flu.

GlaxoSmithKline (GSK) and FDA notified healthcare professionals of a report of the death of a patient with influenza who received Relenza (zanamivir) Inhalation Powder which was solubilized and administered by mechanical ventilation.^[12]

Commercial issues[link]

Although zanamivir was the first neuraminidase inhibitor to the market, it had only a few months lead over the second entrant, oseltamivir (Tamiflu), with an oral tablet formulation.

According to the CDC, Tamiflu, zanamivir’s main competitor, is not as effective at treating the Influenza viruses as zanamivir, especially in H1N1 Seasonal Flu. In fact, tests showed that 99.6% of the tested strains of seasonal H1N1 flu and 0.5% of 2009 pandemic flu were resistant to Tamiflu while there have been absolutely zero flu samples seasonal or pandemic that show any resistance to zanamivir.^{[1] [5][6]}

When first marketed in the US in 1999/2000, zanamivir captured only 25% of the influenza antiviral market, despite a huge promotional campaign. By the end of that season, Tamiflu was outselling zanamivir 3:1. During that season, zanamivir experienced worldwide safety warnings involving the risk of bronchospasm and death. Glaxo then reduced the marketing of zanamivir, and Tamiflu's dominance increased. More than US$20m worth of zanamivir sold by Glaxo in the first US season was returned to the company in the next two seasons because zanamivir's sales to patients were far less than expected.

Biota commenced legal proceedings in 2004 alleging that Glaxo's reduced marketing of zanamivir was a breach of contract. Biota claimed approximately A$700m from Glaxo. After Biota spent four years trying to progress its case, and incurring A$50m in legal costs, the company abandoned the claim in July 2008, recovering only A$20m including legal costs following settlement at mediation. Biota had refused an earlier tactical offer from Glaxo of A$75m plus legal costs.

In August 2006, Germany announced that it would buy 1.7 million doses of zanamivir, as part of its preparation strategy against bird flu. "Germany's purchase shows that countries are starting to take a balanced view of influenza preparedness," says Simon Tucker, head of research at Melbourne-based Biota, where zanamivir was originally developed.^[8]

In April 2009 many cases of swine flu (H1N1 type virus) were reported in US and Mexico. Zanamivir is one of only two drugs that are prescribed to treat it. A study published in June 2009 emphasized the urgent need for augmentation of oseltamivir (Tamiflu) stockpiles, with additional antiviral drugs including zanamivir, based on an evaluation of the performance of these drugs in the scenario that the 2009 H1N1 swine flu neuraminidase (NA) were to acquire the Tamiflu-resistance (His274Tyr) mutation which is currently widespread in 99.6% of all tested seasonal H1N1 strains.^[13]

In January 2011, GSK announced it was commencing Phase III trials for Intravenous zanamivir in a study which will span 20 countries in the Northern and Southern hemispheres. ^[14]

Legal status[link]

The drug is approved for use for the prevention and treatment of influenza in those over the age of 7 in the United States, Canada, European Union and many other countries. It is not recommended for people with respiratory problems and ailments.

Chemistry[link]

After Scheigetz et al.^[15]

References[link]

External links[link]

• The development of Relenza for treatment of influenza^{[dead link]}
• Zanamivir bound to proteins in the PDB
• Drug Information: Zanamivir Inhalation MedlinePlus drug
• Relenza: Consumer Questions and Answers US Food and Drug Administration (FDA)
• Relenza Biota Holdings
• Relenza web site GlaxoSmithKline

Elena Ledda (born 1959 in Selargius) is a Sardinian singer.

Born near Cagliari, she pursued conservatory studies in oboe and voice. Ledda has a dramatic soprano voice suitable for opera, which she originally performed as an artist, but was attracted by the folk singing of her native Sardinia and has chosen a career primarily in that genre of music. She worked with the Cooperativa Teatro di Sardegna in the late 1970s. She has toured and recorded widely at the international level.

She was chosen by Sardinia's top movie director, Gianfranco Cabiddu, to be the leading voice for his renowned live music/cinematic mix project, Sonos de Memoria, featuring old film footage of Sardinia from the 1930s and today's leading musicians from the island playing over the film. Sonos has toured the world, with other well-known Sardinian musicians, such as Paolo Fresu.

A more recent development in 2006 was a new project called "Visioni di Sardegna", written and produced by Elena Ledda's longtime collaborator Mauro Palmas, who had old films of Sardinia from the Luce Institute restored and assembled 18 musicians under the direction of RAI TV director, Rodolfo Roberti. Special guest, renowned Greek singer Savina Yannatou, was invited to feature in the project to give it its unique pan-Mediterranean flavour. The project is ongoing in 2007.

The collaboration with Savina Yannatou, resulted in a series of ten concerts being given at the Half Note club in Athens at the end of March 2006. It met with fabulous critical acclaim and TV interest in Greece. This resulted in a CD being recorded ("Tutti Baci", Lyra 1095) by both of them and featuring Mauro Palmas and Primavera en Salonico.

Among her collaborations, feature the likes of Lester Bowie, Israeli singer Noa, Maria Del Mar Bonet (mallorca), Paolo Fresu, her longtime personal friend as well as Andreas Vollenweider, Don Cherry, and Nana Vasconcelos. In 2005 Elena collaborated with Neapolitan violinist, Lino Cannavacciuolo (Peppe Barra's violinist and original founder of the Solis String Quartet who are now Noa's band of choice) to produce her latest CD "Amargura". A perfect marriage of Sardinian and Neapolitan sounds and rhythms.

The BBC's Andy Kershaw said of Elena "I planned a trip south to make a programme about Sardinian music, almost solely on the evidence of a CD I was given of Elena's voice. We went to Sardinia and I was blown away. Elena and her band make traditional music from Sardinia using all the mainstream instruments, with hardly any 'traditional Sardinian' instruments in sight, yet it sounds so traditional and so not-mainstream. They have achieved a truly unique and refreshing sound. Clearly rooted to Sardinian tradition, yet so modern." The programme, featuring many Sardinian artists can be heard on (fast forward to the 20th minute of part 2 to hear Elena's interview). http://www.bbc.co.uk/radio3/worldmusic/onlocation/ram/corsica2.ram

Her latest recordings due out in 2007 were done with other Sardinian legend, Andrea Parodi who died from cancer in October 2006, before completing the recordings. Elena was asked to sing at Parodi's funeral as they were friends, and both regularly featured in each other's recordings. Effectively, Elena Ledda's 2007 release will be a collaboration which was almost completed in the studio, though sadly Parodi never made it to the end.

Some more fragments of Elena's brilliant band can be heard here [1]

Recordings include:

Ammentos (1979)

Is Arrosas (1984)

Sonos (1989)

Incanti (1993)

Maremannu (2000)

Amargura (2005)

External links[link]

• www.sardinianmusic.com

This biographical article needs additional citations for verification. Please help by adding reliable sources. Contentious material about living persons that is unsourced or poorly sourced must be removed immediately, especially if potentially libelous or harmful. (June 2011)

Fabio Caressa (born on April 18, 1967 in Rome) is a famous Italian journalist and football commentator, broadcasting for SKY Italia.^[1]

He began his career in 1986 and in 1991 was chosen to take part in the commentators team for the newly founded Italian pay tv Tele+, founded by the Canal+ Group. In 1998 he started commenting on Sunday evening Serie A matches, making turns with Massimo Marianella. In 2002 he became the main "voice" of SKY Sport and, together with former Inter Milan star Giuseppe Bergomi, he is now one of the most notorious and appreciated sporting commentators in Italy.

After the World Cup he wrote a book about his experiences during his career and the World cup, entitled Andiamo a Berlino ("We're going to Berlin"), a phrase that Caressa shouted at the end of the World Cup semifinal Germany vs. Italy 0-2 a.e.t., just a few seconds after the goal scored by Alessandro Del Piero, expressing his joy for the qualification of Italy for the final that would be played in Berlin.^[2]

His wife is Italian TV-news journalist Benedetta Parodi: they have two daughters and one son.

References[link]

This article about an Italian writer or poet is a stub. You can help Wikipedia by expanding it. v t e

Emilio Fede
Born	Emilio Fede (1931-06-24) June 24, 1931 (age 81) Barcellona Pozzo di Gotto, Messina, Italy

Emilio Fede (born June 24, 1931) is an Italian anchorman, journalist and writer. He has been the director of TG1 (from 1981 to 1982), a news programme on Raiuno and TG4, (from 1992 to 2012) a news programme on Rete 4.

Biography[link]

Fede was born in Barcellona Pozzo di Gotto, Sicily.

He started his career in the Italian public broadcasting company (RAI) in the early 1950s, and went on to become one of the most popular faces in its news dominant TV market share in Italy. Fede has been the director since 1992 to 2012 of TG4, a news programme on Rete 4, owned by Italian tycoon and former premier Silvio Berlusconi.^[1] Fede has been often accused of excessive partisanship in his news management, to the point of weeping joyfully upon Mr. Berlusconi's 1994 electoral victory.^[2] This partisanship made him earn the nickname "Umilio Fido", that sounds like Humbled Loyal Dog.^[3]

Emilio Fede is, at present, indicted for favouring prostitution of a minor in the framework of the so-called Rubygate scandal, involving Italian Prime Minister Silvio Berlusconi, dental hygienist Nicole Minetti and Karima El Mahrug Ruby Rubacuori

Assault[link]

On the 24th of November 2010 Fede was assaulted at a restaurant in Milan's city centre by Gian Germano Giuliani, the owner of Giuliani Pharmaceuticals.^[4]

Books[link]

• Finché c'è Fede (1997)
• Privé. La vita è un gioco (1998)
• L'invidiato speciale (1999)
• La foglia di fico (2000)
• Samba dei ruffiani (2001)
• La cena dei cretini (2002)
• Ladro d'amore (2003)
• Peluche (2005)
• Fuori Onda (2006)

All published by Arnoldo Mondadori Editore.

References[link]

This article about a European journalist is a stub. You can help Wikipedia by expanding it. v t e

Andrea Agnelli (born 6 December 1975 in Turin) is an Italian businessman and president of Italian football club Juventus F.C..^[1] He is also a board member of FIAT and Exor.

Early life[link]

Agnelli is the son of late Juventus president and senator of the Italian Republic Umberto Agnelli, CEO of Fiat from 1970–1976, and Donna Allegra Caracciolo di Castagneto, first cousin of Marella Agnelli, born Donna Marella Caracciolo di Castagneto. Andrea is the last male member of the family to carry the Agnelli name. He studied at St Clare's in Oxford, England and then at Bocconi University in Milan.

Career[link]

After university, Agnelli started his career in the business world with various companies abroad in England and France including Iveco and Auchan Hypermarché. He also spent several years in Switzerland working in marketing and development for Ferrari Idea and Lausanne-based Philip Morris International.

In May 2010 he was appointed President of Juventus by his first cousin John Elkann, becoming the fourth member of the Agnelli family to run the football club after his father, his uncle and his grandfather.^[2] Elkann had come under criticism from Juventus fans for the club's poor results during the 2009-10 season and many die-hard fans saw Agnelli as the "rightful" heir due to his family's long-time association with the club. Despite entering the job during a period when the club was still dealing with the aftermath of the infamous Calciopoli scandal, he is credited with overseeing the club's transition into the new stadium and balancing their finances in wake of the ongoing recession ravaging Italy.^[3][4] One of his first acts as new president was to appoint Sampdoria duo Giuseppe Marotta as Director of Sport and Luigi Delneri as new coach.

On 22 May 2011, Angelli appointed former player Antonio Conte as the new manager of Juventus, replacing Delneri. The same season Juventus won the first scudetto under Agnelli.^[5].

References[link]