Oseltamivir

Oseltamivir (pronounced ah sell TAH mih veer) is an antiviral drug used in the treatment and prophylaxis of both Influenzavirus A and Influenzavirus B. 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 was the first orally active neuraminidase inhibitor commercially developed.

Oseltamivir is a prodrug (usually administered as phosphate); it is hydrolysed hepatically to the active metabolite, the free carboxylate of oseltamivir (GS4071).

Oseltamivir was developed by Gilead Sciences and is currently marketed by Hoffmann-La Roche (Roche) under the trade name Tamiflu®.

With increasing fears about the potential for a new influenza pandemic, oseltamivir has received substantial media attention. Production capacity is limited, and governments are stockpiling the drug.

Technical information

Indications and dosage

Roche recommendations in the United States

Tamiflu is available from Roche in 75mg capsules and as a powder for aqueous suspension of 12 mg/mL. 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 indicated for the treatment of influenza in patients 1 year and older who have had symptoms for no more than two days. For influenza treatment, the standard dosage for patients 13 years and older is 75 mg twice daily for five days. Dosage for children is by weight.
  • Tamiflu is indicated for prophylaxis of influenza either during a community outbreak or following close contact with an infected individual. 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. Safety and efficacy for prophylaxis has not been established for patients under 13 years old.

The above treatment regimes are based upon studies of normal human influenza.

Dosage for avian flu

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]. Doctors in Vietnam concur, noting that

[A]t least in some patients with influenza A (H5N1) virus infection, treatment with the recommended dose of oseltamivir incompletely suppresses viral replication. Besides allowing the infection to proceed, such incomplete suppression provides opportunities for drug resistance to develop. (de Jong et al. 2005)

Co-administration with probenecid

It has been suggested that co-administration of oseltamivir with another drug called probenecid could dramatically extend the world's limited supply of oseltamivir. Probenecid reduces excretion of oseltamivir's active metabolite. 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 was used in similar fashion during World War II to extend limited supplies of penicillin. The evidence for this interaction comes from a 2002 study by Roche (Hill et al. 2002)[4], but was publicized only in October 2005 by a doctor who had reviewed the data (Butler 2005)[5].

Side effects

Information from Roche

The following information (but not its interpretation) comes from Roche's "Complete Product Information" publication for Tamiflu (intended for the United States).

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. Other adverse reactions were not reported by Tamiflu-treated patients at a markedly higher rate than those treated with placebo.

According to Roche, in the postmarketing period, voluntary reports have possibly linked oseltamivir to the following other adverse reactions:

  • General: Rash, swelling of face or tongue, toxic epidermal necrolysis
  • Digestive: Hepatitis, liver function tests abnormal
  • Cardiac: Arrhythmia
  • Neurologic: Seizure, confusion
  • Metabolic: Aggravation of diabetes

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

Information from Japan: neurological effects and teen deaths

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. 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 February 2004, a 17-year-old male jumped in front of a truck and died after taking one capsule of Tamiflu. In February 2005, a 14-year-old male died after falling nine stories from his condominium building. A third teen reportedly attempted to jump from the window of a building. 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). Roche points out that 32 million doses have been prescribed worldwide, most of them in Japan, and emphasizes the drug's safety.

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. 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). They did recommend adding a warning to prescription information regarding possible rashes.

The authors of this section have yet to find Japan's actual listing of adverse reactions linked to oseltamivir. However, it is known that one adverse reaction added to the Japanese list was haemorrhagic Colitis (bloody diarrhoea)[6].

Chemical synthesis

The reported azide-free Roche synthesis of tamiflu is summarized graphically below:

The synthesis commences from naturally available (−)-shikimic acid. 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. Reductive opening of the ketal under modified Hunter conditions (JOC 1993, 58, 6756) in dichloromethane yields an inseparable mixture of isomeric mesylates. The corresponding epoxide is formed under basic conditions with potassium bicarbonate. 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 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. Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. 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. 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. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. Acidic hydrolysis then removed the imine. 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. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. 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. 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.

Resistance

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. The resistance rate reported during clinical trials up to July 2004 was 0.33% in adults, 4.0% in children, and 1.26% overall. Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme (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). 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). Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. First, children typically have a longer infection period, giving a longer time for resistance to develop. Second, Kiso et al. (2004) claim to have used more rigorous detection techniques than previous studies. 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.

High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. She was being treated with oseltamivir at time of detection (Le et al., 2005; World Health Organization, 2005).

de Jong et al. (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. They suggest that the emergence of a resistant strain may be associated with a patient's clinical deterioration. 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. 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.

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. Kiso et al. (2004) suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic.

The genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. 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. The lack of variation in neuraminidase gives two advantages to oseltamivir and zanamivir, the drugs that target that enzyme. First, these drugs work on a broader spectrum of influenza strains. Second, the development of a robust, resistant virus strain appears to be less likely (Ward et al., 2005). It is worth noting that the oseltamivir-resistant strains detected by Kiso et al. (2004) all appeared within individual children after treatment with oseltamivir - the children did not catch the resistant strains in human-to-human transmission.

Production shortage/shikimic acid

In early-2005, Roche announced a production shortage. (See Pandemic Fears, below). 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. A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as at 2005). Star anise is grown in four provinces in China and harvested between March and May. The shikimic acid is extracted from the seeds in a ten-stage manufacturing process. Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 Tamiflu capsules. Ninety percent of the harvest is already used by Roche in making Tamiflu.

The northern Vietnamese province of Lang Son has 80 km² of star anise.[7]

Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid by means other than star anise extraction. An alternative method for production of the acid involves fermentation of genetically-modified bacteria. Other potential sources of shikimic acid include the ginko tree. 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 actions

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. 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.

Pandemic fears

Oseltamivir, otherwise known as Tamiflu, was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. 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. Though significant, the quantities stockpiled would not have been sufficient to protect the entire population of these countries.

Wikinews has news related to this article: Taiwan to violate Tamiflu patent in order to compensate for vaccine shortage

In October 2005, the Indian drug company Cipla announced their plan to begin manufacture of generic oseltamivir without license from Roche. 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. Cipla argues that it can legally sell oseltamivir to India and 49 other less-developed countries, possibly as early as January 2006. Also in October, it was announced that Roche was in discussions with four generic drug manufacturers about possibly issuing sublicenses to increase production.

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. 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. [10][11][12] Sales were suspended in Hong Kong as well, and on November 8, also in China. Roche said it would instead send all supplies to China's health ministry[13].

On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir[14]. The week before, Thai authorities said they would begin producing oseltamivir by February 2006, claiming that Roche had not patented Tamiflu in Thailand[15].

U.S. Government policy and oseltamivir

In November, 2005, U.S. president George W. 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]. Bush's plan included $1.4 billion for government purchases of anti-viral drugs[17].

Some commentators (e.g., [18]) question the motives of the U.S. 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. 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 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. Previously, Rumsfeld has been implicated in a racketeering lawsuit involving the FDA approval of the artificial sweetner aspartame [20].

On the other hand, at least one Democratic Senator has criticized Bush for not planning to buy enough anti-viral drugs [21].

Personal stockpiling of Tamiflu

The short supply of Tamiflu has prompted some individuals to stockpile the drug. Several American states, including Massachusetts and Colorado, have issued advisories strongly discouraging this practice.

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. 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.

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. 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).

Another argument is that it would be difficult for home users to determine whether illegally-imported Tamiflu is counterfeit. This is genuinely a potential problem, but, in the face of a shortage, some individuals may be willing to face such a risk. In December 2005, 53 packages of fake Tamiflu pills were intercepted by the US Customs Service in South San Francisco. The packages were labeled Generic Tamiflu. 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. However, sophisticated criminals could produce convincing fake packaging in the future. [22][23]

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. This argument lacks face validity, since treatment must begin before such tests results would be available anyway.

A scientist investigating avian influenza stated that he and his colleagues have personal stocks of Tamiflu.

References

  • Schwartz, Nelson . Oct 31, 2005. Rumsfeld's growing stake in Tamiflu: Defense Secretary, ex-chairman of flu treatment rights holder, sees portfolio value growing. Fortune (Accessed on Nov 28, 2005 at http://money.cnn.com/2005/10/31/news/newsmakers/fortune_rumsfeld/?cnn=yes)
  • Pollack, Andrew. Is Bird Flu Drug Really So Vexing? Debating the Difficulty of Tamiflu [News article]. The New York Times (Accessed on November 5, 2005 at http://www.nytimes.com/2005/11/05/business/05tamiflu.html)
  • Butler, D. Wartime tactic doubles power of scarce bird-flu drug [News article]. Nature 2005;438(7064):6. (Accessed on November 2, 2005, at http://www.nature.com/nature/journal/v438/n7064/full/438006a.html)
  • 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. Malik; Hien, Tran Tinh; and Farrar, Jeremy. Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection. New England Journal of Medicine 2005;353(25):2667-2672. (Online at http://content.nejm.org/cgi/content/full/353/25/2667#F1)
  • Hill G, Cihlar T, Oo C, Ho E S, Prior K, Wiltshire H, Barrett J, Liu B, Ward P. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion--correlation of in vivo and in vitro studies. Drug Metabolism and Disposition 2002;30(1):13-19. (Online at: http://dmd.aspetjournals.org/cgi/content/abstract/30/1/13)
  • Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, Kimura K, et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 2004;364(9436):759-65. PMID 15337401
  • 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. Avian flu: Isolation of drug-resistant H5N1 virus. Nature 2005;437(7062):1108.
  • Moscona, Anne. Oseltamivir Resistance - Disabling Our Influenza Defenses [Perspective]. New England Journal of Medicine 2005;353(25):2633-2636.
  • Ward P, Small I, Smith J, Suter P, Dutkowski R. Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother 2005;55(Suppl 1): i5-i21. PMID 15709056
  • World Health Organization. WHO inter-country-consultation: influenza A/H5N1 in humans in Asia: Manila, Philippines, 6-7 May 2005. (Accessed October 12, 2005, at http://www.who.int/csr/resources/publications/influenza/WHO_CDS_CSR_GIP_2005_7/en/.)
  • J. Org. Chem. 1998, 63, 4545-4550. Synthesis of Tamiflu.
  • J. Org. Chem. 2001, 66, 2044-2051. Synthesis of Tamiflu.
  • Chimia 2004, 58, 621.

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A scientist investigating avian influenza stated that he and his colleagues have personal stocks of Tamiflu. Most of his later film and TV credits are for his music. This argument lacks face validity, since treatment must begin before such tests results would be available anyway. Sting has also made appearances on television (including guest spots on The Simpsons and Ally McBeal) and the stage. 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. Notable roles include:. [22][23]. He made his film debut with 1979's Quadrophenia.

However, sophisticated criminals could produce convincing fake packaging in the future. Sting has occasionally ventured into acting. 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. From the Racing Stripes soundtrack. The packages were labeled Generic Tamiflu. From Sacred Love. In December 2005, 53 packages of fake Tamiflu pills were intercepted by the US Customs Service in South San Francisco. From Slicker Than Your Average (Craig David album).

This is genuinely a potential problem, but, in the face of a shortage, some individuals may be willing to face such a risk. From Brand New Day. Another argument is that it would be difficult for home users to determine whether illegally-imported Tamiflu is counterfeit. From The Very Best of Sting & The Police. 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). From Mercury Falling. 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. From Ace Ventura: When Nature Calls soundtrack.

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. From Fields of Gold: The Best of Sting 1984-1994. 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. From Ten Summoner's Tales. Several American states, including Massachusetts and Colorado, have issued advisories strongly discouraging this practice. From The Three Musketeers soundtrack. The short supply of Tamiflu has prompted some individuals to stockpile the drug. Non-album single; soundtrack from the film of the same name.

On the other hand, at least one Democratic Senator has criticized Bush for not planning to buy enough anti-viral drugs [21]. From Ten Summoner's Tales. Previously, Rumsfeld has been implicated in a racketeering lawsuit involving the FDA approval of the artificial sweetner aspartame [20]. (Albums released after going solo.). 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. [2]. 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]). I would want to spend the rest of my life discovering your beautiful country.

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. I like the Hindu religion more than anything else at the moment I have become addicted to India .. Some commentators (e.g., [18]) question the motives of the U.S. In a sense I am more of a Hindu.. Bush's plan included $1.4 billion for government purchases of anti-viral drugs[17]. His words in an interview were:. 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]. In early 2005, Sting proclaimed that he admires Hinduism, wants to spend a lot more time in India and that he loves Indian culture.

president George W. His practice consists primarily of a Ashtanga Vinyasa series, though he has experimented with other forms. In November, 2005, U.S. Soon after, Sting began a regular yoga practice. The week before, Thai authorities said they would begin producing oseltamivir by February 2006, claiming that Roche had not patented Tamiflu in Thailand[15]. However, around 1990 he met Danny Paradise who introduced him to yoga. On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir[14]. To keep physically fit, for years Sting ran (5 miles a day) and did aerobics.

Roche said it would instead send all supplies to China's health ministry[13]. Although Sting was long reputed to be a devotee of tantric sex, he has more recently claimed that it was an interview prank, or a dinner-party joke that took on a life of its own. [10][11][12] Sales were suspended in Hong Kong as well, and on November 8, also in China. In an interview given by Sting, he also referred to what he believed was the natural occurrence of lithium in the brain when one views a sunset, but this may have been a confusion with endorphins. 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. According to some reports, he did this because he wanted to help people who really have this disease. 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. He has written a song entitled "Lithium Sunset" which appears to refer to lithium carbonate, a treatment for the disorder.

Also in October, it was announced that Roche was in discussions with four generic drug manufacturers about possibly issuing sublicenses to increase production. It is unclear whether he was serious or not when he referred to himself as manic-depressive. Cipla argues that it can legally sell oseltamivir to India and 49 other less-developed countries, possibly as early as January 2006. [1] Although Sting also owns properties in Salisbury, Wiltshire, England, and Malibu, California, he currently calls Tuscany his home. 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. Sting's lookalike son Joseph is following in his father's musical footsteps and is a member of the band, Fiction Plane. In October 2005, the Indian drug company Cipla announced their plan to begin manufacture of generic oseltamivir without license from Roche. Sting and Trudie have four children: Bridget Michaela (aka "Mickey", born 1984), Jake (born 1985), Eliot Paulina ("Coco," born 1990), and Giacomo Luke (born 1995).

Though significant, the quantities stockpiled would not have been sufficient to protect the entire population of these countries. In 1982 - shortly after the birth of his second child - Sting separated from Tomelty and began living with actress (and later film producer) Trudie Styler, but the two did not marry until 1992. 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. The couple had two children, Joseph (born 1976), and Fuchsia Katherine (born 1982), before they divorced in 1984. Oseltamivir, otherwise known as Tamiflu, was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. Sting married actress Frances Tomelty, a Catholic from Northern Ireland, on May 1, 1976. 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. Also in 2004, his song "You Will Be My Ain True Love" for the Cold Mountain soundtrack was an Oscar nominee, and was performed at the awards by Alison Krauss, with Sting accompanying on a hurdy-gurdy.

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. Sting embarked on a Sacred Love tour in 2004 with performances by Annie Lennox. 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. His autobiography Broken Music was published in October. Other potential sources of shikimic acid include the ginko tree. Blige and sitar maestro Anoushka Shankar. An alternative method for production of the acid involves fermentation of genetically-modified bacteria. 2003 also saw the release of Sacred Love, an original studio album with racier beats and experiments collaborating with hip-hop artist Mary J.

Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid by means other than star anise extraction. During that performance Sting performed a duet with Gwen Stefani of "Message in a Bottle". The northern Vietnamese province of Lang Son has 80 km² of star anise.[7]. Sting kicked off 2003 with a performance during the Super Bowl's half time show. Ninety percent of the harvest is already used by Roche in making Tamiflu. In the summer, Sumner was awarded the "CBE" - the Commander of the British Empire. Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 Tamiflu capsules. Late in the year, it was announced that The Police would be inducted into the Rock and Roll Hall of Fame in March 2003.

The shikimic acid is extracted from the seeds in a ten-stage manufacturing process. In June, he was inducted into the Songwriters Hall of Fame. Star anise is grown in four provinces in China and harvested between March and May. He won a Golden Globe Award and was nominated for his second Academy Award for his song "Until..." from the film Kate & Leopold. A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as at 2005). 2002 was a year of awards for Sting. 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. All This Time featured jazzy reworkings of Sting favorites such as "Roxanne" and "If You Love Somebody Set Them Free".

(See Pandemic Fears, below). His live album, All This Time, recorded on a moonlit night in Tuscany, was released in November but did not generate healthy sales. In early-2005, Roche announced a production shortage. Later, Sting performed "Fragile" for the fundraiser America: A Tribute to Heroes. (2004) all appeared within individual children after treatment with oseltamivir - the children did not catch the resistant strains in human-to-human transmission. On September 11, he recorded a new live album in Italy, but the Internet simulcast was canceled after the September 11, 2001 terrorist attack. It is worth noting that the oseltamivir-resistant strains detected by Kiso et al. His song "After The Rain Has Fallen" made it into the Top 40.

Second, the development of a robust, resistant virus strain appears to be less likely (Ward et al., 2005). In February 2001, he added another Grammy to his collection. First, these drugs work on a broader spectrum of influenza strains. For his performance, the Arab-American Institute Foundation gave him the Kahlil Gibran Spirit of Humanity Award. The lack of variation in neuraminidase gives two advantages to oseltamivir and zanamivir, the drugs that target that enzyme. At the awards ceremony, he performed "Desert Rose" with Cheb Mami. 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. In 2000, he won Grammy Awards for Brand New Day and the song of the same name.

The genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. The album went Triple Platinum by January 2001. Kiso et al. (2004) suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic. Sting made a (partial) comeback with the September 1999 album Brand New Day, including the Top 40 hits "Brand New Day" and "Desert Rose" (Top 10). 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. (Sting was also featured on Toby Keith's country cover-version of "I'm So Happy I Can't Stop Crying", on Keith's 1997 Dream Walkin' album.) In 1998, he appeared in the Guy Ritchie film Lock, Stock and Two Smoking Barrels. 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. Yet, he reached the Top 40 with two singles the same year with "You Still Touch Me" (June) and "I'm So Happy I Can't Stop Crying" (December).

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. Sting's 1996 album, Mercury Falling debuted strongly, but dropped quickly on the charts. They suggest that the emergence of a resistant strain may be associated with a patient's clinical deterioration. Finally in November, he released a greatest hits compilation called Fields of Gold: The Best of Sting, which was eventually certified Double Platinum. (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. The Berklee College of Music gave him his second honorary doctorate of music degree in May. de Jong et al. In February, he won two more Grammy Awards and was nominated for three more.

She was being treated with oseltamivir at time of detection (Le et al., 2005; World Health Organization, 2005). charts. High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. charts for five weeks and went Platinum; it is to date Sting's only song from his post-Police career to top the U.S. 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. The song stayed at the top of the U.S. Second, Kiso et al. (2004) claim to have used more rigorous detection techniques than previous studies. Together with Bryan Adams and Rod Stewart, they performed the chart-topping song "All For Love" from the film The Three Musketeers.

First, children typically have a longer infection period, giving a longer time for resistance to develop. Sting reached a pinnacle of success in 1994. Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. In May 1993, he released a remix of the classic Police song from the Ghost In The Machine album, "Demolition Man" for the Demolition Man film, starring Sylvester Stallone, Wesley Snipes, Sandra Bullock and Benjamin Bratt. 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). The hit single "Fields of Gold" has since become a "standard", and very well known via versions by Eva Cassidy and Verity Keays. 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). In 1993, he released the album Ten Summoner's Tales, which went Triple Platinum in just over a year.

Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme (Ward et al., 2005). The following year, he married Trudie Styler and was awarded an honorary doctorate degree in music from Northumbria University. The resistance rate reported during clinical trials up to July 2004 was 0.33% in adults, 4.0% in children, and 1.26% overall. The album eventually went Platinum. 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. Sting's 1991 album The Soul Cages was dedicated to his recently deceased father and included the top 10 song "All this Time" and the Grammy winning "Soul Cages". 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. His most high-profile contribution to the human rights cause came in 1988, when he joined a team of major musicians and rising stars — including Peter Gabriel and Bruce Springsteen — assembled under the banner of Amnesty International for the 6-week world Human Rights Now! Tour celebrating the 40th anniversary of the signing of the Universal Declaration of Human Rights.

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. His support for these causes continues to this day. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. With long-time girlfriend Trudie Styler and Raoni Metuktire, a Kayapó Indian leader in Brazil, he founded the Rainforest Foundation to help save the rainforests. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. Throughout the 1980s, Sting strongly supported environmentalism and humanitarian movements, such as Amnesty International. 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. Soon thereafter, in February of 1988, he released Nada Como el Sol — a selection of five songs from Nothing Like the Sun sung (by Sting himself) in Spanish and Portuguese.

Acidic hydrolysis then removed the imine. It eventually went Double Platinum and was recognized as one of the most important rock & roll albums of the 1980s. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. Sting released Nothing Like the Sun (1987), including the hit songs "We'll Be Together" and "Be Still My Beating Heart", dedicated to his recently deceased mother. 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. He also sang the introduction and chorus to "Money for Nothing", a groundbreaking song by Dire Straits. 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. Within a year, it reached Triple Platinum.

Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. It included the hit single "If You Love Somebody Set Them Free". 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. 1985's The Dream of the Blue Turtles, featuring a star-studded cast of jazz musicians, was Sting's first solo album. 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 song was a re-interpretation of a song from the 1920s musical Mr Cinders by Vivian Ellis, and was a surprise top twenty hit. The corresponding epoxide is formed under basic conditions with potassium bicarbonate. In 1982 he released a solo single, "Spread A Little Happiness" from the Dennis Potter television play Brimstone and Treacle.

Reductive opening of the ketal under modified Hunter conditions (JOC 1993, 58, 6756) in dichloromethane yields an inseparable mixture of isomeric mesylates. Sting's participation in The Secret Policeman's Other Ball was the beginning of his growing involvement in raising money and consciousness for political and social causes. 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. His performances were prominently featured in the album and movie of the show and drew major critical attention for Sting. The synthesis commences from naturally available (−)-shikimic acid. The band included Eric Clapton, Jeff Beck, Phil Collins and Bob Geldof all of whom (except Beck) later worked together on "Live Aid". The reported azide-free Roche synthesis of tamiflu is summarized graphically below:. He perfomed solo versions of "Roxanne" and "Message in a Bottle" He also led an all-star band (dubbed "The Secret Police") on his own arrangement of Bob Dylan's "I Shall Be Released".

However, it is known that one adverse reaction added to the Japanese list was haemorrhagic Colitis (bloody diarrhoea)[6].. In September 1981, Sting made his first-ever solo live performance performing on all four nights of the fourth Amnesty International benefit The Secret Policeman's Other Ball at the invitation of producer Martin Lewis. The authors of this section have yet to find Japan's actual listing of adverse reactions linked to oseltamivir. To help promote a greatest hits album that year they also made a re-recording of a new arrangement of one of their hits "Don't Stand So Close to Me '86" as a special bonus track to be included on the album. They did recommend adding a warning to prescription information regarding possible rashes. Their performances were just for the benefit shows and were not part of an intended permanent reunion. 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). The Police performed together at some of the shows on the 1986 Amnesty International A Conspiracy of Hope Tour alongside U2 and other artists.

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. Their last album, Synchronicity which included one of their most successful songs, Every Breath You Take, was released in 1983. Roche points out that 32 million doses have been prescribed worldwide, most of them in Japan, and emphasizes the drug's safety. Although they jumped on the punk bandwagon early in their career, they soon abandoned that sound in favor of reggae-tinged rock and minimalist pop. 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). The group had several chart topping albums and won six Grammy Awards in the early 1980s. A third teen reportedly attempted to jump from the window of a building. In 1977, Sting, Stewart Copeland, and Andy Summers formed the rock/pop band The Police in London.

In February 2005, a 14-year-old male died after falling nine stories from his condominium building. He once performed wearing a black and yellow jersey with hooped stripes that fellow band member Gordon Solomon had noted made him look like a bumblebee, thus he became "Sting." He uses Sting almost exclusively, except on official documents. In February 2004, a 17-year-old male jumped in front of a truck and died after taking one capsule of Tamiflu. He has stated that he gained his nickname while with the Jazzmen. 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. He played with local jazz bands such as the Phoenix Jazzmen and Last Exit. 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. His first music gigs were wherever he could get a job.

The number of adverse reaction reports may be a clue, but these number are not reported by Roche in this document. Before playing music professionally, Sumner worked as a ditch digger and a music teacher at a Catholic primary school. However, given that forms are voluntary, it may be difficult to determine prevalency rates or whether an actual causal relation exists. Both Audrey and Ernest Sumner died of cancer, but Sting did not (or could not) attend either funeral. Postmarketing studies are advantageous because the drug is effectively "tested" on a larger population, and previously missed adverse reactions may be discovered. Philip owns a pub in Newcastle, Angela works for British Airways, and Anita is an artist. According to Roche, in the postmarketing period, voluntary reports have possibly linked oseltamivir to the following other adverse reactions:. He is the oldest of four children and has a brother, Philip, and two sisters, Angela and Anita.

Other adverse reactions were not reported by Tamiflu-treated patients at a markedly higher rate than those treated with placebo. From 1971 to 1974, he attended Northern Counties Teacher Training College. 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. He attended St Cuthbert's grammar School, in Newcastle upon Tyne, and then the University of Warwick, but did not graduate. The following information (but not its interpretation) comes from Roche's "Complete Product Information" publication for Tamiflu (intended for the United States). From an early age, Sumner knew that he wanted to be a musician. 2002)[4], but was publicized only in October 2005 by a doctor who had reviewed the data (Butler 2005)[5]. Ernest was a milkman, and raised his children as Roman Catholics.

The evidence for this interaction comes from a 2002 study by Roche (Hill et al. Sumner was born in Wallsend, near Newcastle upon Tyne, in North-East England to Audrey (a Protestant) and Ernest Sumner (a Catholic via his own mother, Agnes White, whose father was an Irish stevedore). 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. Prior to a distinguished solo career, he was the lead singer, principal composer and bassist of the 1970s/1980s rock band The Police. Probenecid reduces excretion of oseltamivir's active metabolite. Gordon Matthew Sumner, CBE (born October 2, 1951), usually known by his stage name Sting, is an English musician from Newcastle upon Tyne.

It has been suggested that co-administration of oseltamivir with another drug called probenecid could dramatically extend the world's limited supply of oseltamivir. JD, Eddie's father and owner of a bar, in Lock, Stock and Two Smoking Barrels (1998). 2005). The voice of Zarm on Captain Planet and the Planeteers, a 1990s television show. (de Jong et al. Finney, a nightclub owner in Stormy Monday (1988). Besides allowing the infection to proceed, such incomplete suppression provides opportunities for drug resistance to develop. An "heroic officer" in The Adventures of Baron Munchausen (1988).

[A]t least in some patients with influenza A (H5N1) virus infection, treatment with the recommended dose of oseltamivir incompletely suppresses viral replication. Baron Frankenstein in The Bride (1985). Doctors in Vietnam concur, noting that. Mick, a black-marketeer in Plenty (1985). 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]. Feyd-Rautha in the movie Dune (1984). The above treatment regimes are based upon studies of normal human influenza. Martin Taylor, a drifter in Brimstone and Treacle (1982).

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. Ace The Face, the King of The Mods, aka The Bell Boy in the movie adaptation of The Who album Quadrophenia (1979). Tamiflu is available from Roche in 75mg capsules and as a powder for aqueous suspension of 12 mg/mL. 2005 "Taking the Inside Rail" #? US, #? UK. . 2004 "Stolen Car (Take Me Dancing)" #60 UK. Production capacity is limited, and governments are stockpiling the drug. Blidge)" #60 UK.

With increasing fears about the potential for a new influenza pandemic, oseltamivir has received substantial media attention. Mary J. Oseltamivir was developed by Gilead Sciences and is currently marketed by Hoffmann-La Roche (Roche) under the trade name Tamiflu®. 2003 "Whenever I Say Your Name (ft. Oseltamivir is a prodrug (usually administered as phosphate); it is hydrolysed hepatically to the active metabolite, the free carboxylate of oseltamivir (GS4071). 2003 "Send Your Love" #30 UK. Oseltamivir was the first orally active neuraminidase inhibitor commercially developed. Sting) #2 UK.

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. 2003 "Rise & Fall" (Craig David feat. Oseltamivir (pronounced ah sell TAH mih veer) is an antiviral drug used in the treatment and prophylaxis of both Influenzavirus A and Influenzavirus B. 2000 "After the Rain Has Fallen" #31 UK. Chimia 2004, 58, 621. Cheb Mami) #15 UK, #17 US. Synthesis of Tamiflu. 2000 "Desert Rose" (feat.

Chem. 2001, 66, 2044-2051. 1999 "Brand New Day" #13 UK, #100 US. Org. 1997 "Roxanne '97" (remix) (with The Police) #17 UK, #59 US. J. 1996 "I'm So Happy I Can't Stop Crying" #94 US. Synthesis of Tamiflu. 1996 "I Was Brought to My Senses" #31 UK.

Chem. 1998, 63, 4545-4550. 1996 "You Still Touch Me" #27 UK, #60 US. Org. 1996 "Let Your Soul Be Your Pilot" #15 UK, #86 US. J. Sting) #36 UK. (Accessed October 12, 2005, at http://www.who.int/csr/resources/publications/influenza/WHO_CDS_CSR_GIP_2005_7/en/.). 1996 "Spirits in the Material World" (Pato Banton feat.

WHO inter-country-consultation: influenza A/H5N1 in humans in Asia: Manila, Philippines, 6-7 May 2005. Pato Banton) #15 UK. World Health Organization. 1995 "This Cowboy Song" (feat. PMID 15709056. 1994 "When We Dance" #9 UK, #38 US. J Antimicrob Chemother 2005;55(Suppl 1): i5-i21. 1994 "Nothing 'Bout Me" #32 UK.

Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. 1994 "All for Love" (with Bryan Adams and Rod Stewart) #2 UK, #1 US. Ward P, Small I, Smith J, Suter P, Dutkowski R. 1993 "Demolition Man" #21 UK. New England Journal of Medicine 2005;353(25):2633-2636. 1993 "Fields of Gold" #16 UK, #23 US. Oseltamivir Resistance - Disabling Our Influenza Defenses [Perspective]. 1993 "Seven Days" #25 UK.

Moscona, Anne. 1993 "If I Ever Lose My Faith in You" #14 UK, #17 US. Nature 2005;437(7062):1108. 1992 "It's Probably Me" (with Eric Clapton) #30 UK. Avian flu: Isolation of drug-resistant H5N1 virus. 2003 Sacred Love #3 UK, #3 US, US Sales: 1,000,000. 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. 2001 All This Time (live) #3 UK, #32 US, US Sales: 500,000.

PMID 15337401. 1999 At the Movies (Japanese release). Lancet 2004;364(9436):759-65. 1999 Brand New Day #5 UK, #9 US, US Sales: 3,000,000. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. 1997 The Very Best of Sting & The Police #1 UK, #46 US (both positions for the 2002 re-issue). Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, Kimura K, et al. 1996 Mercury Falling #4 UK, #5 US, US Sales: 1,000,000.

(Online at: http://dmd.aspetjournals.org/cgi/content/abstract/30/1/13). 1994 Fields of Gold: The Best of Sting 1984-1994 #2 UK, #7 US, US Sales: 2,000,000. Drug Metabolism and Disposition 2002;30(1):13-19. 1993 Ten Summoner's Tales #2 UK, #2 US, US Sales: 3,000,000. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion--correlation of in vivo and in vitro studies. 1991 Soul Cages #1 UK, #2 US, US Sales: 1,000,000. Hill G, Cihlar T, Oo C, Ho E S, Prior K, Wiltshire H, Barrett J, Liu B, Ward P. 1988 Nada Como el Sol.

(Online at http://content.nejm.org/cgi/content/full/353/25/2667#F1). 1987 Nothing Like the Sun #1 UK, #9 US, US Sales: 2,000,000. New England Journal of Medicine 2005;353(25):2667-2672. 1986 Bring On the Night #16 UK. Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection. 1985 The Dream of the Blue Turtles #3 UK, #2 US, US Sales: 3,000,000. Malik; Hien, Tran Tinh; and Farrar, Jeremy. Sting, who had a small acting career, had a small part in Star Wars Episode V: The Empire Strikes Back as an AT-AT Commander.

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. Sting's song "Desert Rose" is also used as XM Satellite Radio's technical difficulties music. (Accessed on November 2, 2005, at http://www.nature.com/nature/journal/v438/n7064/full/438006a.html). Sting was nominated for Academy Award for his song "You Will Be My Ain True Love" from the movie "Cold Mountain" performed by Alison Krauss. Nature 2005;438(7064):6. Sting famously claimed to have had tantric sex with his wife for 24 hours. Wartime tactic doubles power of scarce bird-flu drug [News article]. Was at one time close to becoming Gil Farrington in a motion picture of the same name, until Sir Ridley Scott terminated the project.

Butler, D. [5]. The New York Times (Accessed on November 5, 2005 at http://www.nytimes.com/2005/11/05/business/05tamiflu.html). A Colombian tree frog was named for him in appreciation of his environmental activities: Hyla stingi. Is Bird Flu Drug Really So Vexing? Debating the Difficulty of Tamiflu [News article]. The song is still widely associated with Jaguar. Pollack, Andrew. Sting's song "Desert Rose" was used in many Jaguar commercials because of the fact that he drove a Jaguar during Desert Rose's music video.

Fortune (Accessed on Nov 28, 2005 at http://money.cnn.com/2005/10/31/news/newsmakers/fortune_rumsfeld/?cnn=yes). He appeared as himself in an episode of The Simpsons, taking part in the charity song for a boy who supposedly fell down a well, "We're Sending Our Love Down The Well". Rumsfeld's growing stake in Tamiflu: Defense Secretary, ex-chairman of flu treatment rights holder, sees portfolio value growing. Sting's fondness for Prokofiev manifested itself subsequently when he served as narrator for Peter and the Wolf: A Prokofiev Fantasy [4] - one of the many versions of Prokofiev's "Peter and the Wolf" that have been recorded by celebrities. Oct 31, 2005. The song "Russians" from The Dream of the Blue Turtles utilized a theme by Russian composer Sergei Prokofiev. Schwartz, Nelson . Sting also made a cameo appearance in the movie, The Adventures of Baron Munchausen [3].

Metabolic: Aggravation of diabetes. Sting and Knopfler remained friends despite this difference between their two music publishers and the fact that half of the writer's share of Knopfler's biggest hit goes to Sting for a contribution of just six musical notes out of the entire song. Neurologic: Seizure, confusion. Even though the prologue only occupies a few seconds at the start of the recording - Sting's music publisher Virgin Music insisted that Sting be credited (and paid) as though he had written half of the entire song. Cardiac: Arrhythmia. Sting came up with the musical motif to use for the words - and it was (probably consciously) musically identical to the melody line in his own Police song "Don't Stand So Close To Me" from the album Zenyatta Mondatta. Digestive: Hepatitis, liver function tests abnormal. The prologue to the Dire Straits' recording "Money for Nothing" that features Sting singing the words "I want my MTV" was at the invitation of Dire Straits leader Mark Knopfler.

General: Rash, swelling of face or tongue, toxic epidermal necrolysis. Sting was also the inspiration for the comic book character John Constantine (from Hellblazer). Safety and efficacy for prophylaxis has not been established for patients under 13 years old. In his Live8 performance he changed the lyrics to his song 'Every Breath You Take' from "I'll be watching you” to "we'll be watching you" — meant for the men of the G8. 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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