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. Almost every year at least one, but often several such films are produced and released, resulting in Cinderella becoming a work of literature with one of the largest numbers of film adaptations ascribed to it, perhaps rivaled only by the sheer number of films that have been adapted from or based on Bram Stoker's novel Dracula. This argument lacks face validity, since treatment must begin before such tests results would be available anyway. Over the decades since the invention of motion pictures, literally hundreds of films have been made that are either direct adaptations or have plots loosely based on the story of Cinderella. 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. Her traditional line "Cinderella, you shall go to the ball!" has passed into common usage from gay culture where the meme of the "glamorous transformation" is a source of fascination and humor. [22][23]. The fairy Godmother must magically create a coach (from a pumpkin), footmen (from mice) and a beautiful dress for Cinderella in order for her to go to the ball.

However, sophisticated criminals could produce convincing fake packaging in the future. There are also added characters such as Buttons (Baron Hardup's servant, and Cinderella's friend) and Dandini (the Prince's right-hand man, the character and even his name coming from Rossini's opera). 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. The stepmother's own daughters are the Ugly sisters who are jealous of Cinderella and cruel to her. The packages were labeled Generic Tamiflu. In the pantomime form Cinderella's father (Baron Hardup) is under the thumb of the stepmother. In December 2005, 53 packages of fake Tamiflu pills were intercepted by the US Customs Service in South San Francisco. The subject of Cinderella is very common for British and Australian pantomimes.

This is genuinely a potential problem, but, in the face of a shortage, some individuals may be willing to face such a risk. The story of "Cinderella" has formed the basis of many works:. Another argument is that it would be difficult for home users to determine whether illegally-imported Tamiflu is counterfeit. Detractors of such princess brides argue that the wedding is not solely about the bride; nevertheless, many wedding gown retailers appeal, directly or indirectly, to the Cinderella ideal. 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). A bride with the Cinderella mindset believes that the dress and the occasion exist in order that she may be transformed for the day into a beautiful princess. 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. Cinderella, along with the more general "princess," are shorthand for a particular approach to weddings and Western wedding attire, especially the white dress.

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. For example, a girl from a wealthy household who has been ordered to wash the dishes as a fulfilment of her once a month chores would be deemed a Cinderella; a fallen princess who has finally met with tough reality. 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. Others are called Cinderella if they tend to quietly complain. Several American states, including Massachusetts and Colorado, have issued advisories strongly discouraging this practice. Some girls are described as a Cinderella if they are meek and immediately submissive to stern orders. The short supply of Tamiflu has prompted some individuals to stockpile the drug. The term Cinderella has evolved from its storybook beginnings to become the name for a variety of female personalities.

On the other hand, at least one Democratic Senator has criticized Bush for not planning to buy enough anti-viral drugs [21]. Earlier, less self-consciously instructive Cinderellas have more revealing mythic content. Previously, Rumsfeld has been implicated in a racketeering lawsuit involving the FDA approval of the artificial sweetner aspartame [20]. The anachronism of a supposed skin-color sensitivity in Egypt itself is revealing. 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. As a document, this reveals some contemporary American approaches to historicism, cultural multiplicity, racism, and educating for a spirit of tolerance. 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]). Based partly on fact (a slave named Rhodopis did marry Pharaoh Amasis) and partly on folk legends, this story is remarkable for its details of life in ancient Egypt and for the Egyptian-style illustrations".

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. He searches for, and finds, the girl. Some commentators (e.g., [18]) question the motives of the U.S. Eventually, one of her rosy-gold slippers is carried to the pharaoh's court. Bush's plan included $1.4 billion for government purchases of anti-viral drugs[17]. An example of the "uses of Cinderella" is presented by Shirley Climo, The Egyptian Cinderella (1989), aimed at young children: "Rhodopis, a Greek slave girl living in Egypt, is teased by the servants about her coloring. 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]. Refactoring continues.

president George W. Thus serious uses come from what appears on the surface to be a trivial wish-fulfilment narrative. In November, 2005, U.S. Mythographers return to Cinderella for hints of the social ethos embodied in it, and the familiar story proves to be a useful case example for young students beginning to understand how myth works. The week before, Thai authorities said they would begin producing oseltamivir by February 2006, claiming that Roche had not patented Tamiflu in Thailand[15]. Each social group, in re-telling "Cinderella," has emphasized or suppressed individual elements and has given them interpretations that are especially relevant within each society. On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir[14]. Instead, cultural elements ("memes" to some writers) may be disentangled from the Cinderella tale.

Roche said it would instead send all supplies to China's health ministry[13]. In more recent times, as Freud's concepts have found more support as myth and poetry than as neurological science, it has seemed to mythographers less useful to explain one myth in terms of another myth. [10][11][12] Sales were suspended in Hong Kong as well, and on November 8, also in China. The idea that "Cinderella" embodies myth elements was explored in The Uses of Enchantment (1989) by Bruno Bettelheim, who made many connections to the principles of Freudian psychology. 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. Humorous retellings of the story sometimes use the twist of having the shoes turn out to also fit somebody completely unsuitable, such as an amorous old crone. 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. The translation of the story into cultures with different standards of beauty has left the significance of Cinderella's shoe size unclear, and resulted in the implausibility of Cinderella's feet being of a unique size for no particular reason.

Also in October, it was announced that Roche was in discussions with four generic drug manufacturers about possibly issuing sublicenses to increase production. Small feet were an important aspect of beauty in Chinese culture, leading to practices such as foot binding. Cipla argues that it can legally sell oseltamivir to India and 49 other less-developed countries, possibly as early as January 2006. The original Chinese version of the story emphasized that Cinderella (or Yè Xiàn [葉羨] as she was called; known in the West as Yeh-Shen) had the smallest feet in the land. 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. Interpreters unaware of the value attached to glass in 17th century France and perhaps troubled by sartorial impracticalities, have suggested that Perrault's "glass slipper" (pantoufle de verre) had been a "fur slipper" (pantoufle de vair) in some unidentified earlier version of the tale, and that Perrault or one of his sources confused the words; however, most scholars believe the glass slipper was a deliberate piece of poetic invention on Perrault's part. In October 2005, the Indian drug company Cipla announced their plan to begin manufacture of generic oseltamivir without license from Roche. The glass slipper is unique to Perrault's version; in other versions of the tale it may be made of other materials (in the version recorded by the Brothers Grimm, German: Aschenbroedel and Aschenputtel, for instance, it is gold) and in still other tellings, it is not a slipper but a ring or a bracelet that gives the prince the key to Cinderella's identity.

Though significant, the quantities stockpiled would not have been sufficient to protect the entire population of these countries. The midnight curfew is also absent in many versions; Cinderella leaves the ball to get home before her stepmother and stepsisters, or she is simply tired. 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. Thus her mother (sometimes represented as a bird) is the supernatural force who assists the girl to find her prince. Oseltamivir, otherwise known as Tamiflu, was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. It is also worth noting that in some versions of the story there is no fairy godmother; rather Cinderella's dress and shoes come from a tree that grows over her mother's grave. 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. The evil stepsisters are sometimes punished for their deception by having their eyes pecked out by crows, or in other cases forgiven.

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. In all variants, Cinderella arrives and proves her identity by fitting into the slipper (in some cases she has kept the other, as in the Disney retelling). 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. The second stepsister fits into the slipper by cutting off her heel, but the same eagle gives her away. Other potential sources of shikimic acid include the ginko tree. In the German telling of the story, the first stepsister fits into the slipper by cutting off a toe, but a magical eagle tells the prince to notice the blood dripping from the slipper, and he returns the false bride to her mother. An alternative method for production of the acid involves fermentation of genetically-modified bacteria. Cinderella's stepmother and stepsisters (in some versions just the stepsisters) conspire to win the prince's hand for one of them.

Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid by means other than star anise extraction. He declares that he will marry only the girl whose petite foot fits into the slipper. The northern Vietnamese province of Lang Son has 80 km² of star anise.[7]. In her haste, she loses a glass slipper which the prince finds. Ninety percent of the harvest is already used by Roche in making Tamiflu. However, on the third (or only) night, she loses track of the time and must flee the castle before her disguise vanishes. Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 Tamiflu capsules. In the three-ball version, Cinderella keeps a close watch on the time the first two nights and is able to leave without difficulty.

The shikimic acid is extracted from the seeds in a ten-stage manufacturing process. Unfortunately, the magic comes to an end at the first stroke of midnight. Star anise is grown in four provinces in China and harvested between March and May. In some versions of the tale, there are three balls, though most tellings mention only one. A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as at 2005). Forced into a life of domestic servitude, hence the nickname, as she was forced to tend the fireplace, Cinderella accepts the help of her attendant spirit ("fairy godmother") who transforms her to attend a royal ball and attract the attention of the handsome prince. 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. The familiar plot revolves around a girl deprived of her rightful station in the family and given the cruel nickname "Cinderella" by her horrible stepmother and step-sisters.

(See Pandemic Fears, below). . In early-2005, Roche announced a production shortage. The best-known version was written by the French author, Charles Perrault in 1697, based on a common folk tale earlier recorded by Giambattista Basile as La Gatta Cennerentola in 1634, but the animated film from Walt Disney Productions, (see Cinderella (1950 film)) has become the standard contemporary version despite the fact that it somewhat sanitises the original plotline. (2004) all appeared within individual children after treatment with oseltamivir - the children did not catch the resistant strains in human-to-human transmission. It appeared in The Miscellaneous Record of You Yang (酉阳杂俎) by Tuan Ch'eng-Shih, a book which dates from the Tang Dynasty. It is worth noting that the oseltamivir-resistant strains detected by Kiso et al. The earliest version of the story originated in China around AD 860.

Second, the development of a robust, resistant virus strain appears to be less likely (Ward et al., 2005). Cinderella is a popular fairy tale embodying a classic folk tale myth-element of unjust oppression/triumphant reward, which received literally hundreds of tellings before modern times. First, these drugs work on a broader spectrum of influenza strains. The Ash Girl by Timberlake Wertenbaker. The lack of variation in neuraminidase gives two advantages to oseltamivir and zanamivir, the drugs that target that enzyme. I was a Rat! or The Scarlet Slippers by Philip Pullman. 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. Confessions of an Ugly Stepsister by Gregory Maguire.

The genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. Phoenix and Ashes by Mercedes Lackey. Kiso et al. (2004) suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic. The Glass Slipper by Eleanor Farjeon. 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. Just Ella by Margaret Peterson Haddix. 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. Ella Enchanted by Gail Carson Levine.

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. Witches Abroad by Terry Pratchett. They suggest that the emergence of a resistant strain may be associated with a patient's clinical deterioration. Ella Enchanted, starring Minnie Driver and Anne Hathaway (2004). (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. Cinderelmo, a Cinderella story featuring Sesame Street's Elmo and Keri Russell. de Jong et al. A Cinderella Story, released July 16, 2004, is a modernization of the classic fairy tale featuring Hilary Duff and Chad Michael Murray.

She was being treated with oseltamivir at time of detection (Le et al., 2005; World Health Organization, 2005). Cinderella, a 2000 British production set in mid-20th century and starring Kathleen Turner. High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. Ever After, 1998, starring Drew Barrymore. 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. Cinderella, 1997 with Brandy and Whitney Houston. Second, Kiso et al. (2004) claim to have used more rigorous detection techniques than previous studies. Cindy, made for television, 1978.

First, children typically have a longer infection period, giving a longer time for resistance to develop. The Slipper and the Rose, a 1976 British musical film starring Gemma Craven and Richard Chamberlain. Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. Tři oříšky pro Popelku (Three Nuts for Cinderella), Czech movie 1973. 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). Cinderfella, 1960, notorious because the main character is a man, played by Jerry Lewis. 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). Cinderella, 1957 with Julie Andrews.

Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme (Ward et al., 2005). The Glass Slipper, 1955, with Leslie Caron and Michael Wilding. The resistance rate reported during clinical trials up to July 2004 was 0.33% in adults, 4.0% in children, and 1.26% overall. A Cinderella III is set to be released in 2006. 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. A direct-to-video sequel, Cinderella II: Dreams Come True, was released in 2002. 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. Cinderella, an animated feature released on February 14, 1950, now considered one of Disney's "classics".

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. Cinderella (Зо́лушка), Russian musical film of 1947, 84 min, by Lenfilm studios. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. This film was about 7 minutes long. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. Cinderella, an animated Laugh-O-Gram produced by Walt Disney, first released on December 6, 1922. 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. Cinderella, 1911 silent film, starring Florence La Badie.

Acidic hydrolysis then removed the imine. Cinderella, the 1899 first ever film version produced in France by Georges Méliès. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. Into the Woods by Stephen Sondheim (Cinderella is only a small part of this plot). 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. Mister Cinders, which was filmed in 1934. 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. In 2005 the Rodgers and Hammerstein musical was adapted for the stage, also starring Paolo Montalban and with an ethnically diverse cast.

Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. Cinderella (1997) featuring Brandy, Paolo Montalban, Whitney Houston, Whoopi Goldberg, Victor Garber, Bernadette Peters, and Jason Alexander, considered by Amazon.com to be weak despite its diverse cast. 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. Cinderella (1965) featuring Lesley Ann Warren, Stuart Damon, Ginger Rogers, Walter Pidgeon, and Celeste Holm, considered by Amazon.com to be the best TV version. 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. Cinderella (1957) featuring Julie Andrews, Jon Cypher, Kaye Ballard, Alice Ghostley and Edith Adams. The corresponding epoxide is formed under basic conditions with potassium bicarbonate. Cinderella by Rodgers and Hammerstein, which was produced for television three times:

    .

    Reductive opening of the ketal under modified Hunter conditions (JOC 1993, 58, 6756) in dichloromethane yields an inseparable mixture of isomeric mesylates. Cinderella by Sergei Prokofiev. 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. Aschenbroedel by Johann Strauss II. The synthesis commences from naturally available (−)-shikimic acid. La Cenicienta by Jorge Peña Hen. The reported azide-free Roche synthesis of tamiflu is summarized graphically below:. Cendrillon by Jules Massenet.

    However, it is known that one adverse reaction added to the Japanese list was haemorrhagic Colitis (bloody diarrhoea)[6].. La Cenerentola by Gioacchino Rossini. 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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