Carrie Underwood

Carrie Marie Underwood (born March 10, 1983) is an American country singer who rose to fame as the winner of the fourth season of American Idol.

Early years

Carrie Underwood was born in Muskogee, Oklahoma and raised in a farm in Checotah, Oklahoma.

At the age of 13, her manager at the time tried to get a recording contract at Capitol Records, but due to management changes at Capitol it never materialized.

Underwood graduated from Checotah High School in 2001 as salutatorian. Underwood attended Northeastern State University, where she majored in mass communication and is a member of Sigma Sigma Sigma sorority. She also competed in numerous beauty pageants at the university and was selected as Miss NSU runner-up in 2004.

Idol

Underwood's musical influences include pop, but are predominantly country; she stated during Idol auditions that her favorite singer is Martina McBride. On the April 20 elimination show, Underwood demonstrated her ability to play the guitar. She can also play piano and yodel, the latter of which was demonstrated on the Tonight Show the night after she won.

After singing Martina McBride's "Independence Day" Simon Cowell said he couldn't believe no one has discovered her yet.

On the March 22 show, after a performance of Heart's "Alone", Simon Cowell said, "Carrie, you're not just the girl to beat, you're the person to beat. I will make a prediction, not only will you win this competition, but you will sell more records than any other previous 'Idol' winner." Cowell went on to say on the March 30 show that she has the "it factor" that will make her a star.

On her last song of the night in the final two, Carrie's spectacular performance of "Angels Brought Me Here" had Simon saying, "I think you've done enough to win the competition." On May 25, 2005, she became the fourth winner of American Idol, beating Southern rocker Bo Bice, and she joins Kelly Clarkson and Clay Aiken as the only contestants who have never been one of the "bottom three" singers during any week's results. During the season, Constantine Maroulis tried to flirt with her but she refused to go out with him.

Post-Idol career

As part of her title, Underwood gained a recording contract with Arista Records; her first single, "Inside Your Heaven", was released on June 14, 2005. The single debuted at #1 on the Billboard Hot 100, with first-week sales of 170,000 copies, and briefly stopped Mariah Carey's run at #1 with "We Belong Together." One week later, runner-up, Bo Bice, released his version of the song, which debuted at #2. Underwood's version was shunned by country radio reaching a peak of #59 on the country charts. [1] The B-side is "Independence Day", a cover of the Martina McBride hit.

Some Hearts CD Cover

Underwood performed a well-received "The Star Spangled Banner" before Game 4 of the 2005 NBA Finals at the Palace of Auburn Hills in Michigan. In the same year, she starred in ads for Hershey's Chocolate. The commercials have Underwood singing Hershey jingles like the jingles for Hershey's, Kit Kat and Almond Joy. She is also wearing vintage Hershey T-shirts that feature Hershey's, Almond Joy, Kit Kat, Reeses and other chocolate brand logos. The T-Shirts are now available to buy with proofs of purchase. Underwood is also the latest spokesperson for Skechers shoes, following in the footsteps of Britney Spears and Christina Aguilera.

Underwood's second single, "Jesus, Take The Wheel" was made available for radio airplay on October 18, 2005. It received so much airplay that it debuted at #39 on the Billboard Country Chart in its first week, setting a record. It is currently ranked at #1 in its thirteenth week on that chart. The single also debuted at #48 on the Billboard Hot 100 where it currently sits at #26 after reaching a peak at #25.

Her initial album release, entitled Some Hearts, hit store shelves on November 15, 2005. [2] On that same day, she presented an award and performed "Jesus, Take The Wheel" at the 39th Country Music Association awards in New York City. When the week's sales figures were tabulated, Some Hearts entered the Billboard 200 chart with 315,000 copies sold. The large first week sales of Some Hearts made it #1 on the Billboard Top Country Albums chart and the biggest debut of any country artist since the advent of the SoundScan system in 1990.

In December 2005, Underwood was named "Oklahoman of the Year" by Oklahoma Today magazine.

On January 9th 2006, Some Hearts was certified Double Platinum by the RIAA with shipments of over 2 million units, making it the fastest-selling debut country album in the history of Nielsen SoundScan.[3]

"Don't Forget to Remember Me" was recently announced as the next single. [4]

Personal life

As of November 2005, Carrie Underwood is currently dating Northeastern State University student Chad Eagleton. Pictures of the two of them surfaced when Chad Eagelton posted pictures of him and Carrie at the Maxim after party on his Facebook account. During American Idol she dated Drake Clark, also from Northeastern State University. Carrie Underwood and Drake Clark agreed to break it off since the two were not spending enough time together.

She is a big sports fan. Her favorite sports teams are the Boston Red Sox, Dallas Cowboys, and Los Angeles Lakers.

List of Underwood's performances on American Idol

Auditions and pre-performance rounds

  • St. Louis Auditions - "I Can't Make You Love Me" (Original Artist: Bonnie Raitt)
  • Hollywood 1 - "Young Hearts (Run Free)" (O.A.: Candi Staton)"
  • Hollywood 2 - "Independence Day" (O.A.: Martina McBride)

Live performances

  • Semi-Final Performance 1 (Women Top 12) - "Could've Been" (O.A.: Tiffany)
  • Semi-Final Performance 2 (Women Top 10) - "Piece of My Heart" (O.A.: Faith Hill's version of Janis Joplin's classic)
  • Semi-Final Performance 3 (Women Top 8) - "Because You Love Me" (O.A.: Jo Dee Messina)
  • Finals Top 12 Performance (Songs of the 60's) - "When Will I Be Loved" (O.A.: The Everly Brothers)
  • Finals Top 11 Performance (Billboard #1's) - "Alone" (O.A.: Heart)
  • Finals Top 10 Performance (Songs of the 90's) - "Independence Day" (O.A.: Martina McBride)
  • Finals Top 9 Performance (Broadway Musicals) - "Hello Young Lovers" (O.A.: Johnny Mathis)
  • Finals Top 8 Performance (Songs from Contestants' Birthyear) - "Love Is a Battlefield" (O.A.: Pat Benatar)
  • Finals Top 7 Performance (70's Dance Music) - "MacArthur Park" (O.A.: Donna Summer's version of Richard Harris' hit)
  • Finals Top 6 Performance (Songs of the 21st Century) - "When God Fearin' Women Get the Blues" (O.A.: Martina McBride)
  • Finals Top 5 Performance 1 (Leiber and Stoller Songs) - "Trouble" (O.A.: Elvis Presley)
  • Finals Top 5 Performance 2 (Billboard top 40) - "Bless the Broken Road" (O.A.: Rascal Flatts' version of Marcus Hummon's "Bless the Broken Road")
  • Finals Top 4 Performance 1 (Nashville Songs) - "Sin Wagon" (O.A.: The Dixie Chicks)
  • Finals Top 4 Performance 2 (Gamble and Huff Songs) - "If You Don't Know Me by Now" (O.A.: Harold Melvin & the Blue Notes)
  • Finals Top 3 Performance 1 (Clive Davis' choice) - "Crying" (O.A.: Roy Orbison)
  • Finals Top 3 Performance 2 (Performer's choice) - "Making Love out of Nothing at All" (O.A.: Air Supply)
  • Finals Top 3 Performance 3 (Judges' choice) - "Man! I Feel Like a Woman!" (O.A.: Shania Twain)
  • Finals Top 2 Performance 1 (new song written for AI) - "Inside Your Heaven"
  • Finals Top 2 Performance 2 (favorite from season) - "Independence Day" (O.A.: Martina McBride)
  • Finals Top 2 Performance 3 (song originally written for Australian Idol) - "Angels Brought Me Here" (O.A.: Guy Sebastian)
  • Final Results Show (duet with Bo Bice) - "Up Where We Belong" (O.A.: Jennifer Warnes and Joe Cocker)
  • Final Results Show (performance with Rascal Flatts) - "Bless the Broken Road"
  • Final Results Show (post-win performance of first single) - "Inside Your Heaven"

Discography

Albums

Singles

Awards

2005 Billboard Music Awards

  • Top-Selling Hot 100 Song of the Year: "Inside Your Heaven/Independence Day," Carrie Underwood (Won)
  • Country Single Sales Artist of the Year: Carrie Underwood (Won)
  • Top-Selling Country Single of the Year: "Inside Your Heaven/Independence Day," Carrie Underwood (Won)

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2005 Billboard Music Awards. A scientist investigating avian influenza stated that he and his colleagues have personal stocks of Tamiflu. Her favorite sports teams are the Boston Red Sox, Dallas Cowboys, and Los Angeles Lakers. This argument lacks face validity, since treatment must begin before such tests results would be available anyway. She is a big sports fan. A fourth purported problem is that the H5N1 virus can be reliably diagnosed only in a small number of labs around the world; therefore, there is no way for home users to know whether flu-like symptoms are the result of avian flu or a more benign ailment. Carrie Underwood and Drake Clark agreed to break it off since the two were not spending enough time together. [22][23].

During American Idol she dated Drake Clark, also from Northeastern State University. However, sophisticated criminals could produce convincing fake packaging in the future. Pictures of the two of them surfaced when Chad Eagelton posted pictures of him and Carrie at the Maxim after party on his Facebook account. Roche officials know of only one instance of counterfeit Tamiflu appearing outside of the United States: incorrectly-labeled pills found in Holland, which contained only Vitamin C and lactose. As of November 2005, Carrie Underwood is currently dating Northeastern State University student Chad Eagleton. The packages were labeled Generic Tamiflu. [4]. In December 2005, 53 packages of fake Tamiflu pills were intercepted by the US Customs Service in South San Francisco.

"Don't Forget to Remember Me" was recently announced as the next single. This is genuinely a potential problem, but, in the face of a shortage, some individuals may be willing to face such a risk. On January 9th 2006, Some Hearts was certified Double Platinum by the RIAA with shipments of over 2 million units, making it the fastest-selling debut country album in the history of Nielsen SoundScan.[3]. Another argument is that it would be difficult for home users to determine whether illegally-imported Tamiflu is counterfeit. In December 2005, Underwood was named "Oklahoman of the Year" by Oklahoma Today magazine. Many stockpilers will only have ten 75 mg pills (the current recommended dosage for oseltamivir), but this may be insufficient for the treatment of H5N1 (de Jong 2005). The large first week sales of Some Hearts made it #1 on the Billboard Top Country Albums chart and the biggest debut of any country artist since the advent of the SoundScan system in 1990. In the New England Journal of Medicine, Moscona (2005) argues that the use of personal stockpiles of oseltamivir could result in the administration of low dosages, allowing for the development of drug-resistant virus strains.

When the week's sales figures were tabulated, Some Hearts entered the Billboard 200 chart with 315,000 copies sold. Ethical arguments are sometimes made: Why should affluent people (or nations) have preferred access to antiviral medications? Illegal importation may divert the drug from poorer countries where the risk of avian influenza is actually higher. [2] On that same day, she presented an award and performed "Jesus, Take The Wheel" at the 39th Country Music Association awards in New York City. One argument against individual stockpiling is that limited drugs should be kept for more strategic or ethical deployment, that is, to hard-hit areas, to people in critical roles (e.g., healthcare and government workers), to people vulnerable to seasonal flu, or to people who actually have come down with avian influenza. Her initial album release, entitled Some Hearts, hit store shelves on November 15, 2005. Several American states, including Massachusetts and Colorado, have issued advisories strongly discouraging this practice. The single also debuted at #48 on the Billboard Hot 100 where it currently sits at #26 after reaching a peak at #25. The short supply of Tamiflu has prompted some individuals to stockpile the drug.

It is currently ranked at #1 in its thirteenth week on that chart. On the other hand, at least one Democratic Senator has criticized Bush for not planning to buy enough anti-viral drugs [21]. It received so much airplay that it debuted at #39 on the Billboard Country Chart in its first week, setting a record. Previously, Rumsfeld has been implicated in a racketeering lawsuit involving the FDA approval of the artificial sweetner aspartame [20]. Underwood's second single, "Jesus, Take The Wheel" was made available for radio airplay on October 18, 2005. The rise in Gilead's share prices from $35 to $57 per share will have added between $2.5 million to $15.5 million to Rumsfeld's net worth. Underwood is also the latest spokesperson for Skechers shoes, following in the footsteps of Britney Spears and Christina Aguilera. Rumsfeld is a former chairman of Gilead, and federal disclosure forms indicate that he owns between $5 million and $25 million in Gilead stock (Schwartz 2005 [19]).

The T-Shirts are now available to buy with proofs of purchase. government's endorsement and planned purchase of oseltamivir, noting Secretary of State Donald Rumsfeld's close ties to Gilead Sciences, rightsholder to the Tamiflu patent. She is also wearing vintage Hershey T-shirts that feature Hershey's, Almond Joy, Kit Kat, Reeses and other chocolate brand logos. Some commentators (e.g., [18]) question the motives of the U.S. The commercials have Underwood singing Hershey jingles like the jingles for Hershey's, Kit Kat and Almond Joy. Bush's plan included $1.4 billion for government purchases of anti-viral drugs[17]. In the same year, she starred in ads for Hershey's Chocolate. Bush requested Congress to fund $7.1 billion in emergency spending for flu pandemic prepardness (the Senate had already passed an $8.1 billion bill)[16].

Underwood performed a well-received "The Star Spangled Banner" before Game 4 of the 2005 NBA Finals at the Palace of Auburn Hills in Michigan. president George W. [1] The B-side is "Independence Day", a cover of the Martina McBride hit. In November, 2005, U.S. Underwood's version was shunned by country radio reaching a peak of #59 on the country charts. The week before, Thai authorities said they would begin producing oseltamivir by February 2006, claiming that Roche had not patented Tamiflu in Thailand[15]. The single debuted at #1 on the Billboard Hot 100, with first-week sales of 170,000 copies, and briefly stopped Mariah Carey's run at #1 with "We Belong Together." One week later, runner-up, Bo Bice, released his version of the song, which debuted at #2. On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir[14].

As part of her title, Underwood gained a recording contract with Arista Records; her first single, "Inside Your Heaven", was released on June 14, 2005. Roche said it would instead send all supplies to China's health ministry[13]. During the season, Constantine Maroulis tried to flirt with her but she refused to go out with him. [10][11][12] Sales were suspended in Hong Kong as well, and on November 8, also in China. On her last song of the night in the final two, Carrie's spectacular performance of "Angels Brought Me Here" had Simon saying, "I think you've done enough to win the competition." On May 25, 2005, she became the fourth winner of American Idol, beating Southern rocker Bo Bice, and she joins Kelly Clarkson and Clay Aiken as the only contestants who have never been one of the "bottom three" singers during any week's results. It said that, when distribution resumes in Canada, the remaining available drug will be saved for use in high-risk settings like long-term care facilities and hospitals. I will make a prediction, not only will you win this competition, but you will sell more records than any other previous 'Idol' winner." Cowell went on to say on the March 30 show that she has the "it factor" that will make her a star. In late-October 2005, Roche announced that it was suspending shipments to pharmacies in the United States and Canada until the North American seasonal flu outbreak began, to address concerns about private stockpiling and to preserve supplies for seasonal influenza.

On the March 22 show, after a performance of Heart's "Alone", Simon Cowell said, "Carrie, you're not just the girl to beat, you're the person to beat. Also in October, it was announced that Roche was in discussions with four generic drug manufacturers about possibly issuing sublicenses to increase production. After singing Martina McBride's "Independence Day" Simon Cowell said he couldn't believe no one has discovered her yet. Cipla argues that it can legally sell oseltamivir to India and 49 other less-developed countries, possibly as early as January 2006. She can also play piano and yodel, the latter of which was demonstrated on the Tonight Show the night after she won. Most patent laws allow governments to authorize supply from generic companies, subject to remuneration to patent owners to address public health problems, including emergencies, although Roche has annouced its intention to remain the sole supplier of the drug. On the April 20 elimination show, Underwood demonstrated her ability to play the guitar. In October 2005, the Indian drug company Cipla announced their plan to begin manufacture of generic oseltamivir without license from Roche.

Underwood's musical influences include pop, but are predominantly country; she stated during Idol auditions that her favorite singer is Martina McBride. Though significant, the quantities stockpiled would not have been sufficient to protect the entire population of these countries. She also competed in numerous beauty pageants at the university and was selected as Miss NSU runner-up in 2004. In response to the epidemic, various governments – including those of the United Kingdom, Canada, United States and Australia – stockpiled quantities of oseltamivir in preparation for a possible pandemic. Underwood attended Northeastern State University, where she majored in mass communication and is a member of Sigma Sigma Sigma sorority. Oseltamivir, otherwise known as Tamiflu, was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. Underwood graduated from Checotah High School in 2001 as salutatorian. Veterinary investigation of its use for canine parvo [8] and canine flu [9]is ongoing, but many shelters and rescue groups have reported great success employing Tamiflu in the early stages of these illnesses.

At the age of 13, her manager at the time tried to get a recording contract at Capitol Records, but due to management changes at Capitol it never materialized. Tamiflu appears to be active against canine parvovirus, feline panleukopenia, the canine respiratory complex known as "kennel cough," and the emerging disease dubbed "canine flu", an equine virus that began affecting dogs in 2005. Carrie Underwood was born in Muskogee, Oklahoma and raised in a farm in Checotah, Oklahoma. In addition, quinic acid, derived from the bark of the cinchona tree of Zaire, is a potential alternative base material for the production of oseltamivir. . Other potential sources of shikimic acid include the ginko tree. Carrie Marie Underwood (born March 10, 1983) is an American country singer who rose to fame as the winner of the fourth season of American Idol. An alternative method for production of the acid involves fermentation of genetically-modified bacteria.

Top-Selling Country Single of the Year: "Inside Your Heaven/Independence Day," Carrie Underwood (Won). Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid by means other than star anise extraction. Country Single Sales Artist of the Year: Carrie Underwood (Won). The northern Vietnamese province of Lang Son has 80 km² of star anise.[7]. Top-Selling Hot 100 Song of the Year: "Inside Your Heaven/Independence Day," Carrie Underwood (Won). Ninety percent of the harvest is already used by Roche in making Tamiflu. Final Results Show (post-win performance of first single) - "Inside Your Heaven". Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 Tamiflu capsules.

Final Results Show (performance with Rascal Flatts) - "Bless the Broken Road". The shikimic acid is extracted from the seeds in a ten-stage manufacturing process. Final Results Show (duet with Bo Bice) - "Up Where We Belong" (O.A.: Jennifer Warnes and Joe Cocker). Star anise is grown in four provinces in China and harvested between March and May. Finals Top 2 Performance 3 (song originally written for Australian Idol) - "Angels Brought Me Here" (O.A.: Guy Sebastian). A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as at 2005). Finals Top 2 Performance 2 (favorite from season) - "Independence Day" (O.A.: Martina McBride). According to Roche, the major bottleneck in oseltamivir production is the availability of shikimic acid, which cannot be economically synthesized and is only effectively isolated from Chinese star anise, an ancient cooking spice; although most autotrophic organisms produce shikimic acid, the isolation yield is low.

Finals Top 2 Performance 1 (new song written for AI) - "Inside Your Heaven". (See Pandemic Fears, below). Finals Top 3 Performance 3 (Judges' choice) - "Man! I Feel Like a Woman!" (O.A.: Shania Twain). In early-2005, Roche announced a production shortage. Finals Top 3 Performance 2 (Performer's choice) - "Making Love out of Nothing at All" (O.A.: Air Supply). (2004) all appeared within individual children after treatment with oseltamivir - the children did not catch the resistant strains in human-to-human transmission. Finals Top 3 Performance 1 (Clive Davis' choice) - "Crying" (O.A.: Roy Orbison). It is worth noting that the oseltamivir-resistant strains detected by Kiso et al.

Finals Top 4 Performance 2 (Gamble and Huff Songs) - "If You Don't Know Me by Now" (O.A.: Harold Melvin & the Blue Notes). Second, the development of a robust, resistant virus strain appears to be less likely (Ward et al., 2005). Finals Top 4 Performance 1 (Nashville Songs) - "Sin Wagon" (O.A.: The Dixie Chicks). First, these drugs work on a broader spectrum of influenza strains. Finals Top 5 Performance 2 (Billboard top 40) - "Bless the Broken Road" (O.A.: Rascal Flatts' version of Marcus Hummon's "Bless the Broken Road"). The lack of variation in neuraminidase gives two advantages to oseltamivir and zanamivir, the drugs that target that enzyme. Finals Top 5 Performance 1 (Leiber and Stoller Songs) - "Trouble" (O.A.: Elvis Presley). This means that there are relatively few variations, and there is also evidence that variations that do occur tend to be less "fit." Thus, mutations that convey resistance to oseltamivir may also tend to cripple the virus by giving it an otherwise less-functional enzyme.

Finals Top 6 Performance (Songs of the 21st Century) - "When God Fearin' Women Get the Blues" (O.A.: Martina McBride). The genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. Finals Top 7 Performance (70's Dance Music) - "MacArthur Park" (O.A.: Donna Summer's version of Richard Harris' hit). Kiso et al. (2004) suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic. Finals Top 8 Performance (Songs from Contestants' Birthyear) - "Love Is a Battlefield" (O.A.: Pat Benatar). Resistance is of concern in the scenario of an influenza pandemic, since resistance is more likely to develop due to the potentially longer duration of infection by novel viruses. Finals Top 9 Performance (Broadway Musicals) - "Hello Young Lovers" (O.A.: Johnny Mathis). Moscona (2005) gives a good overview of the resistance issue, and says that personal stockpiles of Tamiflu could lead to under-dosage and thus the emergence of resistant strains of H5N1.

Finals Top 10 Performance (Songs of the 90's) - "Independence Day" (O.A.: Martina McBride). They also note that the recommended dosage of oseltamivir does not always completely suppress viral replication, a situation that could favor the emergence of resistant strains. Finals Top 11 Performance (Billboard #1's) - "Alone" (O.A.: Heart). They suggest that the emergence of a resistant strain may be associated with a patient's clinical deterioration. Finals Top 12 Performance (Songs of the 60's) - "When Will I Be Loved" (O.A.: The Everly Brothers). (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. Semi-Final Performance 3 (Women Top 8) - "Because You Love Me" (O.A.: Jo Dee Messina). de Jong et al.

Semi-Final Performance 2 (Women Top 10) - "Piece of My Heart" (O.A.: Faith Hill's version of Janis Joplin's classic). She was being treated with oseltamivir at time of detection (Le et al., 2005; World Health Organization, 2005). Semi-Final Performance 1 (Women Top 12) - "Could've Been" (O.A.: Tiffany). High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. Hollywood 2 - "Independence Day" (O.A.: Martina McBride). Third, the dosage regimen in Japan is different from that of other nations, and some children may have been given a suboptimal dosage of oseltamivir. Hollywood 1 - "Young Hearts (Run Free)" (O.A.: Candi Staton)". Second, Kiso et al. (2004) claim to have used more rigorous detection techniques than previous studies.

Louis Auditions - "I Can't Make You Love Me" (Original Artist: Bonnie Raitt). First, children typically have a longer infection period, giving a longer time for resistance to develop. St. Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. This rate was similar to another study where resistant isolates of H1N1 influenza virus were found in 16.3% of another cohort of Japanese children (Ward et al., 2005). Mutant H3N2 influenza A virus isolates resistant to oseltamivir were found in 18% of a group of 50 Japanese children treated with oseltamivir (Kiso et al., 2004).

Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme (Ward et al., 2005). The resistance rate reported during clinical trials up to July 2004 was 0.33% in adults, 4.0% in children, and 1.26% overall. As with other antivirals, resistance to the agent was expected with widespread use of oseltamivir, though the emergence of resistant viruses was expected to be less frequent than with amantadine or rimantadine. Roche has other routes to Tamiflu that do not involve the use of (−)-shikimic acid as a chiral pool starting material, such as a Diels-Alder route involving furan and ethyl acrylate or an isophthalic acid route, which involves catalytic hydrogenation and enzymatic desymmetrization.

It is noted that the synthesis avoids the use of potentially explosive azide reagents and intermediates; however, the synthesis actually used by Roche uses azides. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. Selective acylation with acetic anhydride (under buffered conditions, the 5-amino group is protonated owing to a considerable difference in pKa, 4.2 vs 7.9, preventing acetylation) yields the desired N-acetylated product in crystalline form upon extractive workup.

Acidic hydrolysis then removed the imine. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. Mesylation, followed by removal of the solid byproduct triethylamine hydrochloride, results in an intermediate that was poised to undergo aziridination upon transimination with another equivalent of allylamine. The aminoalcohol was converted directly to the corresponding allyl-diamine in an interesting cascade sequence that commences with the unselective imination of benzaldehyde with azeotropic water removal in methyl tert-butyl ether.

Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. The water-immiscible solvents methyl tert-butyl ether and acetonitrile are used to simplify the workup procedure, which involved stirring with 1 M aqueous ammonium sulfate. Using the inexpensive Lewis acid magnesium bromide diethyl etherate (commonly prepared fresh by the addition of magnesium turnings to 1,2-dibromoethane in benzene:diethyl ether), the epoxide is opened with allyl amine to yield the corresponding 1,2-amino alcohol. The corresponding epoxide is formed under basic conditions with potassium bicarbonate.

Reductive opening of the ketal under modified Hunter conditions (JOC 1993, 58, 6756) in dichloromethane yields an inseparable mixture of isomeric mesylates. The 3,4-pentylidene acetal mesylate is prepared in three steps: esterification with ethanol and thionyl chloride; ketalization with para-toluenesulfonic acid and 3-pentanone; and mesylation with triethylamine and methanesulfonyl chloride. The synthesis commences from naturally available (−)-shikimic acid. The reported azide-free Roche synthesis of tamiflu is summarized graphically below:.

However, it is known that one adverse reaction added to the Japanese list was haemorrhagic Colitis (bloody diarrhoea)[6].. The authors of this section have yet to find Japan's actual listing of adverse reactions linked to oseltamivir. They did recommend adding a warning to prescription information regarding possible rashes. The Committee stated that there was insufficient evidence to claim a causal link between oseltamivir use and the deaths of 12 Japanese children (only two from neurological problems).

On November 18, 2005, a previously-scheduled Advisory Committee to the United States Food and Drug Administration (FDA) met to reconsider the pediatric safety of Tamiflu; a six-page report was issued: Pediatric Safety Update for Tamiflu. Roche points out that 32 million doses have been prescribed worldwide, most of them in Japan, and emphasizes the drug's safety. The two deaths were reported to the Japanese health ministry by Chugai Pharmaceutical Co., a corporation half-owned by Roche, which distributes Tamiflu in Japan (Japan Times November 13, 2005; Reuters Nov 14, 2005). A third teen reportedly attempted to jump from the window of a building.

In February 2005, a 14-year-old male died after falling nine stories from his condominium building. In February 2004, a 17-year-old male jumped in front of a truck and died after taking one capsule of Tamiflu. According to Japan's Pharmaceuticals and Medical Devices Agency, there were 64 cases of psychological disorders linked to the drug between fiscal years 2000 and 2004. In May 2004, the safety division of Japan's health ministry ordered changes to the literature accompanying oseltamivir to add neurological and psychological disorders as possible side effects, including: impaired consciousness, abnormal behavior, and hallucinations.

The number of adverse reaction reports may be a clue, but these number are not reported by Roche in this document. However, given that forms are voluntary, it may be difficult to determine prevalency rates or whether an actual causal relation exists. Postmarketing studies are advantageous because the drug is effectively "tested" on a larger population, and previously missed adverse reactions may be discovered. According to Roche, in the postmarketing period, voluntary reports have possibly linked oseltamivir to the following other adverse reactions:.

Other adverse reactions were not reported by Tamiflu-treated patients at a markedly higher rate than those treated with placebo. In the clinical trials performed by Roche (comparing roughly 2,700 individuals given Tamiflu with 2,650 given placebo), nausea and vomiting were the most frequent adverse reactions reported. The following information (but not its interpretation) comes from Roche's "Complete Product Information" publication for Tamiflu (intended for the United States). 2002)[4], but was publicized only in October 2005 by a doctor who had reviewed the data (Butler 2005)[5].

The evidence for this interaction comes from a 2002 study by Roche (Hill et al. Probenecid was used in similar fashion during World War II to extend limited supplies of penicillin. 500 mg of probenecid given every six hours doubles oseltamivir's maximum blood concentration and also doubles the time that oseltamivir stays in the blood, multiplying a patient's overall exposure to the drug 2.5-fold. Probenecid reduces excretion of oseltamivir's active metabolite.

It has been suggested that co-administration of oseltamivir with another drug called probenecid could dramatically extend the world's limited supply of oseltamivir. 2005). (de Jong et al. Besides allowing the infection to proceed, such incomplete suppression provides opportunities for drug resistance to develop.

[A]t least in some patients with influenza A (H5N1) virus infection, treatment with the recommended dose of oseltamivir incompletely suppresses viral replication. Doctors in Vietnam concur, noting that. Peter Hobby (of the World Health Organization) has suggested that Vietnam should investigate and test a higher dosage and longer treatment with Tamiflu for patients with avian influenza[2][3]. The above treatment regimes are based upon studies of normal human influenza.

According to prescription information by Roche for the United States[1], Tamiflu usage is indicated for both the treatment and prophylaxis of influenza at the following dosages. Tamiflu is available from Roche in 75mg capsules and as a powder for aqueous suspension of 12 mg/mL. . Production capacity is limited, and governments are stockpiling the drug.

With increasing fears about the potential for a new influenza pandemic, oseltamivir has received substantial media attention. Oseltamivir was developed by Gilead Sciences and is currently marketed by Hoffmann-La Roche (Roche) under the trade name Tamiflu®. Oseltamivir is a prodrug (usually administered as phosphate); it is hydrolysed hepatically to the active metabolite, the free carboxylate of oseltamivir (GS4071). Oseltamivir was the first orally active neuraminidase inhibitor commercially developed.

Like zanamivir, oseltamivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells. Oseltamivir (pronounced ah sell TAH mih veer) is an antiviral drug used in the treatment and prophylaxis of both Influenzavirus A and Influenzavirus B. Chimia 2004, 58, 621. Synthesis of Tamiflu.

Chem. 2001, 66, 2044-2051. Org. J. Synthesis of Tamiflu.

Chem. 1998, 63, 4545-4550. Org. J. (Accessed October 12, 2005, at http://www.who.int/csr/resources/publications/influenza/WHO_CDS_CSR_GIP_2005_7/en/.).

WHO inter-country-consultation: influenza A/H5N1 in humans in Asia: Manila, Philippines, 6-7 May 2005. World Health Organization. PMID 15709056. J Antimicrob Chemother 2005;55(Suppl 1): i5-i21.

Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. Ward P, Small I, Smith J, Suter P, Dutkowski R. New England Journal of Medicine 2005;353(25):2633-2636. Oseltamivir Resistance - Disabling Our Influenza Defenses [Perspective].

Moscona, Anne. Nature 2005;437(7062):1108. Avian flu: Isolation of drug-resistant H5N1 virus. Le Q M, Kiso M, Someya K, Sakai Y T, Nguyen T H, Nguyen K H L, Pham N D, Ngyen H H, Yamada S, Muramoto Y, Horimoto T, Takada A, Goto H, Suzuki T, Suzuki Y, Kawaoka Y.

PMID 15337401. Lancet 2004;364(9436):759-65. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, Kimura K, et al.

(Online at: http://dmd.aspetjournals.org/cgi/content/abstract/30/1/13). Drug Metabolism and Disposition 2002;30(1):13-19. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion--correlation of in vivo and in vitro studies. Hill G, Cihlar T, Oo C, Ho E S, Prior K, Wiltshire H, Barrett J, Liu B, Ward P.

(Online at http://content.nejm.org/cgi/content/full/353/25/2667#F1). New England Journal of Medicine 2005;353(25):2667-2672. Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection. Malik; Hien, Tran Tinh; and Farrar, Jeremy.

de Jong, Menno D.; Thanh, Tran Tan; Khanh, Truong Huu; Hien, Vo Minh; Smith, Gavin J.D.; Chau, Nguyen Vinh; Cam, Bach Van; Qui, Phan Tu; Ha, Do Quang; Guan, Yi; Peiris, J.S. (Accessed on November 2, 2005, at http://www.nature.com/nature/journal/v438/n7064/full/438006a.html). Nature 2005;438(7064):6. Wartime tactic doubles power of scarce bird-flu drug [News article].

Butler, D. The New York Times (Accessed on November 5, 2005 at http://www.nytimes.com/2005/11/05/business/05tamiflu.html). Is Bird Flu Drug Really So Vexing? Debating the Difficulty of Tamiflu [News article]. Pollack, Andrew.

Fortune (Accessed on Nov 28, 2005 at http://money.cnn.com/2005/10/31/news/newsmakers/fortune_rumsfeld/?cnn=yes). Rumsfeld's growing stake in Tamiflu: Defense Secretary, ex-chairman of flu treatment rights holder, sees portfolio value growing. Oct 31, 2005. Schwartz, Nelson .

Metabolic: Aggravation of diabetes. Neurologic: Seizure, confusion. Cardiac: Arrhythmia. Digestive: Hepatitis, liver function tests abnormal.

General: Rash, swelling of face or tongue, toxic epidermal necrolysis. Safety and efficacy for prophylaxis has not been established for patients under 13 years old. Standard dosage is 75 mg once daily for patients aged 13 and older, which has been shown to be safe and effective for up to six weeks. Tamiflu is indicated for prophylaxis of influenza either during a community outbreak or following close contact with an infected individual.

Dosage for children is by weight. For influenza treatment, the standard dosage for patients 13 years and older is 75 mg twice daily for five days. Tamiflu is indicated for the treatment of influenza in patients 1 year and older who have had symptoms for no more than two days.

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