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. For descriptions of the Earth in (science) fiction, see Earth in fiction. This argument lacks face validity, since treatment must begin before such tests results would be available anyway. See Spaceship Earth and Gaia theory.. 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. Earth has also been described as a massive spaceship, with a life support system that requires maintenance, or as having a biosphere that forms one large organism. [22][23]. A photo taken of Earth by Voyager 1 inspired Carl Sagan to describe the planet as a "Pale Blue Dot".

However, sophisticated criminals could produce convincing fake packaging in the future. The technological developments of the latter half of the 20th century are widely considered to have altered the public's perception of the Earth. 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. Surveying, the determination of locations and distances, and to a somewhat lesser extent navigation, the determination of position and direction, have developed alongside cartography and geography, providing and suitably quantifying the requisite information. The packages were labeled Generic Tamiflu. Cartography, the study and practice of mapmaking, and vicariously geography, have historically been the disciplines devoted to depicting the Earth. In December 2005, 53 packages of fake Tamiflu pills were intercepted by the US Customs Service in South San Francisco. Prior to the introduction of space flight, this belief was countered with deductions based on observations of the secondary effects of the Earth's shape and parallels drawn with the shape of other planets.

This is genuinely a potential problem, but, in the face of a shortage, some individuals may be willing to face such a risk. In the past there were varying levels of belief in a flat Earth because of this, but ancient Greek philosophers and, in the Middle Ages, thinkers such as Thomas Aquinas knew that the Earth was a sphere. Another argument is that it would be difficult for home users to determine whether illegally-imported Tamiflu is counterfeit. Since Earth is rather large, it is not immediately obvious to the naked eye viewing from the surface that it is an oblate spheroid, bulging slightly at the equator and slightly flattened at the poles. 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). In Norse mythology, the Earth goddess Jord was the mother of Thor and the daughter of Annar. 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. As the patroness of fertility, her element is Earth.

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. The Chinese Earth goddess Hu-Tu is similar to Gaia, the deification of the Earth. 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. Earth has often been personified as a deity, in particular a goddess (see Gaia and Mother Earth). Several American states, including Massachusetts and Colorado, have issued advisories strongly discouraging this practice. The United Nations is primarily an international discussion forum with only limited ability to pass and enforce laws. The short supply of Tamiflu has prompted some individuals to stockpile the drug. There is a worldwide general international organization, the United Nations.

On the other hand, at least one Democratic Senator has criticized Bush for not planning to buy enough anti-viral drugs [21]. Independent sovereign nations claim all of the land surface except for some segments of Antarctica. Previously, Rumsfeld has been implicated in a racketeering lawsuit involving the FDA approval of the artificial sweetner aspartame [20]. Earth does not have a sovereign government with planet-wide authority. 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. There are 267 administrative divisions, including nations, dependent areas, other, and miscellaneous entries. 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 southernmost is the Amundsen-Scott South Pole Station, in Antarctica, almost exactly at the South Pole.

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. The northernmost settlement in the world is Alert, Ellesmere Island, Canada. Some commentators (e.g., [18]) question the motives of the U.S. See also space colonization. Bush's plan included $1.4 billion for government purchases of anti-viral drugs[17]. Out of those only twelve humans have ever walked on a world other than Earth: the men of Apollo 11, 12, 14, 15, 16 and 17, who walked on the Moon between 1969 and 1972. 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 total, about 400 people have been outside Earth (in space) as of 2004.

president George W. During the exchange there are more, and sometimes others are also traveling briefly above the atmosphere. In November, 2005, U.S. The station crew is replaced with new personnel every six months. The week before, Thai authorities said they would begin producing oseltamivir by February 2006, claiming that Roche had not patented Tamiflu in Thailand[15]. Two humans are presently in orbit around Earth on board the International Space Station. On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir[14]. Coastal areas constitute the highest density.

Roche said it would instead send all supplies to China's health ministry[13]. It is estimated that only 1/8th of the surface of the Earth is suitable for humans to live on - 3/4 is covered by oceans, and half of the landmass is unsuitable, being desert, high mountain, etc. [10][11][12] Sales were suspended in Hong Kong as well, and on November 8, also in China. Nearly all humans currently reside on Earth: 6,411,000,000 inhabitants (January 5, 2005 est.). 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. Most of the growth is expected to take place in developing nations. In late-October 2005, Roche announced that it was suspending shipments to pharmacies in the United States and Canada until the North American seasonal flu outbreak began, to address concerns about private stockpiling and to preserve supplies for seasonal influenza. On 25 February 2005 the United Nations Population Division issued revised estimates and projected that the world's population will reach 7 billion by 2013 and swell to 9.1 billion in 2050.

Also in October, it was announced that Roche was in discussions with four generic drug manufacturers about possibly issuing sublicenses to increase production. Long-term climate alteration due to enhancement of the greenhouse effect by human industrial carbon dioxide emissions is an increasing concern, the focus of intense study and debate. Cipla argues that it can legally sell oseltamivir to India and 49 other less-developed countries, possibly as early as January 2006. Large areas are subject to man-made pollution of the air and water, acid rain and toxic substances, loss of vegetation (overgrazing, deforestation, desertification), loss of wildlife, species extinction, soil degradation, soil depletion, erosion, and introduction of invasive species. 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. Many places are subject to earthquakes, landslides, tsunamis, volcanic eruptions, tornadoes, sinkholes, floods, droughts, and other calamities and disasters. In October 2005, the Indian drug company Cipla announced their plan to begin manufacture of generic oseltamivir without license from Roche. Large areas are subject to extreme weather such as (tropical cyclones), hurricanes, or typhoons that dominate life in those areas.

Though significant, the quantities stockpiled would not have been sufficient to protect the entire population of these countries. Irrigated land: 2,481,250 km2 (1993 est.). 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 exploitation of non-renewable resources by human civilization has become a subject of significant controversy in modern environmentalism movements. Oseltamivir, otherwise known as Tamiflu, was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. Some of these resources, such as mineral fuels, are difficult to replenish on a short time scale, called non-renewable resources. 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. Elevation extremes: (measured relative to sea level).

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. Ocean currents, particularly the spectacular thermohaline circulation which distributes heat energy from the equatorial oceans to the polar regions, are important determinators of climate. 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. Precipitation patterns vary widely, ranging from several metres of water per year to less than a millimetre. Other potential sources of shikimic acid include the ginko tree. Two large areas of polar climates separated by two rather narrow temperate zones from a wide equatorial band of tropical to subtropical climates. An alternative method for production of the acid involves fermentation of genetically-modified bacteria. Terrestrial biomes lying within the Arctic and Antarctic Circles are relatively barren of plant and animal life, while most of the more populous biomes lie near the Equator.

Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid by means other than star anise extraction. On land, biomes are separated primarily by latitude. The northern Vietnamese province of Lang Son has 80 km² of star anise.[7]. The biosphere is divided into a number of biomes, inhabited by broadly similar flora and fauna. Ninety percent of the harvest is already used by Roche in making Tamiflu. This biosphere is generally believed to have begun evolving about 3.5 billion (3.5×109) years ago. Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 Tamiflu capsules. The planet's lifeforms are sometimes said to form a "biosphere".

The shikimic acid is extracted from the seeds in a ten-stage manufacturing process. Earth is the only place in the universe where life is absolutely known to exist, and some scientists believe that biospheres might be rare. Star anise is grown in four provinces in China and harvested between March and May. Maritime claims: see United Nations Convention on the Law of the Sea. A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as at 2005). Coastline: 356,000 km. 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. Land boundaries: the land boundaries in the world total 251,480 km (not counting shared boundaries twice).

(See Pandemic Fears, below). Area:. In early-2005, Roche announced a production shortage. Continents, Oceans. (2004) all appeared within individual children after treatment with oseltamivir - the children did not catch the resistant strains in human-to-human transmission. Biggest geographic subdivision. It is worth noting that the oseltamivir-resistant strains detected by Kiso et al. Time Zones, Coordinates.

Second, the development of a robust, resistant virus strain appears to be less likely (Ward et al., 2005). Map references:. First, these drugs work on a broader spectrum of influenza strains. Earth also has at least one co-orbital asteroid, 3753 Cruithne. The lack of variation in neuraminidase gives two advantages to oseltamivir and zanamivir, the drugs that target that enzyme. This hypothesis explains (among other things) the Moon's relative lack of iron and volatile elements, and the fact that its composition is nearly identical to that of the Earth's crust. 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 most widely accepted theory of the Moon's origin, the giant impact theory, states that it was formed from the collision of a Mars-size protoplanet with the early Earth.

The genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. This allows total eclipses and annular eclipses to occur on Earth. Kiso et al. (2004) suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic. The Moon is just far enough away to have, when seen from Earth, very nearly the same apparent angular size as the Sun (the Sun is 400 times larger, but the Moon is 400 times closer). 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. This remains a controversial subject, however, and further studies of Mars—which shares Earth's rotation period and axial tilt, but not its large moon or liquid core—may provide additional insight. 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. Planetary scientists who have studied the effect claim that this might kill all large animal and higher plant life.

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. One pole would be pointed directly toward the Sun during summer and directly away during winter. They suggest that the emergence of a resistant strain may be associated with a patient's clinical deterioration. If Earth's axis of rotation were to approach the plane of the ecliptic, extremely severe weather could result, as this would make seasonal differences extreme. (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. Some theorists believe that, without this stabilization against the torques applied by the Sun and planets to the Earth's equatorial bulge, the rotational axis might be chaotically unstable, as it appears to be with Mars. de Jong et al. Paleontological evidence and computer simulations show that Earth's axial tilt is stabilised by tidal interactions with the Moon.

She was being treated with oseltamivir at time of detection (Le et al., 2005; World Health Organization, 2005). The Moon may dramatically affect the development of life by taming the weather. High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. As the Moon orbits Earth, different parts of its face are illuminated by the Sun, leading to the lunar phases: The dark part of the face is separated from the light part by the solar terminator. 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. As a result, it always presents the same face to the planet. Second, Kiso et al. (2004) claim to have used more rigorous detection techniques than previous studies. The same effect on the Moon has led to its tidal locking: Its rotation period is the same as the time it takes to orbit the Earth.

First, children typically have a longer infection period, giving a longer time for resistance to develop. The gravitational attraction between the Earth and Moon cause the tides on Earth. Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. The natural satellites orbiting other planets are called "moons", after Earth's Moon. 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). With the exception of Pluto's Charon, it is the largest moon in the Solar system relative to the size of its planet. 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). The Moon, sometimes called 'Luna', is a relatively large terrestrial planet-like satellite, whose diameter is about one-quarter of the Earth's.

Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme (Ward et al., 2005).
. The resistance rate reported during clinical trials up to July 2004 was 0.33% in adults, 4.0% in children, and 1.26% overall. The Earth is sometimes referred to as the Third Planet from the Sun because, of the nine planets of our solar system, Earth is the third closest planet to the sun. 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. For other eras, see precession and Milankovitch cycles. 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. In modern times, Earth's perihelion is always about January 3, and aphelion is about July 4 (near the winter and summer solstices, which are on about December 21 and June 21, respectively).

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. Also, the rotational velocity varies, a phenomenon known as length of day variation. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. The polar motion is quasi-periodic, containing an annual component and a component with a 14-month period called the Chandler wobble. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. In a reference frame attached to the solid body of the Earth, its rotation is also slightly irregular due to polar motion. 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. These motions are caused by the differential attraction of Sun and Moon on the Earth's equatorial bulge, due to its oblateness.

Acidic hydrolysis then removed the imine. In an inertial reference frame, the Earth's axis undergoes a slow precessional motion with a period of some 25,800 years, as well as a nutation with a main period of 18.6 years. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. The Hill sphere (sphere of influence) of the Earth is about 1.5 Gm (930 thousand miles) in radius, within which one natural satellite (the Moon) comfortably orbits. Mesylation, followed by removal of the solid byproduct triethylamine hydrochloride, results in an intermediate that was poised to undergo aziridination upon transimination with another equivalent of allylamine. The orbital and axial planes are not precisely aligned: Earth's axis is tilted some 23.5 degrees against the Earth-Sun plane (which causes the seasons); and the Earth-Moon plane is tilted about 5 degrees against the Earth-Sun plane (otherwise there would be an eclipse every month). 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. Viewed from Earth's north pole, the motion of Earth, its moon and their axial rotations are all counterclockwise.

Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. When combined with the Earth-Moon system's common revolution around the Sun, the period of the synodic month, from new moon to new moon, is 29.53 days. 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. Earth has one natural satellite, the Moon, which revolves with the Earth around a common barycenter, from fixed star to fixed star, every 27.32 days. 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 orbital speed of the Earth averages about 30 km/s (108,000 km/h), which is enough to cover one Earth diameter (~12,700 km) in 7 minutes, and one distance to the Moon (384,000 km) in 4 hours. The corresponding epoxide is formed under basic conditions with potassium bicarbonate. From Earth, this gives an apparent movement of the Sun with respect to the stars at a rate of about 1 °/day, i.e., a Sun or Moon diameter every 12 hours, eastward.

Reductive opening of the ketal under modified Hunter conditions (JOC 1993, 58, 6756) in dichloromethane yields an inseparable mixture of isomeric mesylates. Earth orbits the Sun every 365.2564 mean solar days (1 sidereal year). 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. From Earth the main apparent motion of celestial bodies in the sky (except meteors which are within the atmosphere and low-orbiting satellites) is the movement to the west at a rate of 15 °/h = 15'/min, i.e., a Sun or Moon diameter every two minutes. The synthesis commences from naturally available (−)-shikimic acid. It takes the Earth 23 hours, 56 minutes and 4.091 seconds (1 sidereal day) to rotate around the axis connecting the north pole and the south pole. The reported azide-free Roche synthesis of tamiflu is summarized graphically below:.
.

However, it is known that one adverse reaction added to the Japanese list was haemorrhagic Colitis (bloody diarrhoea)[6].. The geologic component layers of the Earth are located at the following depths below surface:. 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. The biosphere is a tiny layer in this composition and is usually not considered part of the physical layers of the Earth. Roche points out that 32 million doses have been prescribed worldwide, most of them in Japan, and emphasizes the drug's safety. Its components are the atmosphere, the hydrosphere, the crust, the mantle, and its core. 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 Earth consists of several atmospheric, hydrologic, and mainly geologic layers. 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. Although a link to such Indo-European languages has not been proved, several Semitic languages have similar-sounding words for Earth: aard in Arabic, irtsitu in Akkadian, araa in Aramaic, erets in Phoenician (which appears in the Mesha Stele), and ארץ (arets, or erets when followed by a noun modifier) in Hebrew. In February 2004, a 17-year-old male jumped in front of a truck and died after taking one capsule of Tamiflu. tierra in Spanish). 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. Taking into account metathesis, we can find cognates of the word Earth in the Latin terra and in the modern Romance languages (i.e. 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. It is derived from Old English eorðe.

The number of adverse reaction reports may be a clue, but these number are not reported by Roche in this document. The root also has cognates in extinct languages such as ertha in Old Saxon and ert (meaning 'ground') in Middle Irish. However, given that forms are voluntary, it may be difficult to determine prevalency rates or whether an actual causal relation exists. Examples in modern tongues include aarde in Dutch, Erde in German and arde in Arabic. Postmarketing studies are advantageous because the drug is effectively "tested" on a larger population, and previously missed adverse reactions may be discovered. The English word Earth has cognates in many modern as well as defunct - including ancient - languages. According to Roche, in the postmarketing period, voluntary reports have possibly linked oseltamivir to the following other adverse reactions:. Besides words derived from Terra, such as terrestrial, terms that refer to the Earth include tellur- (telluric, tellurion, from the goddess Terra's alternate name, Tellūs) and geo- (geography, geocentric, geothermal; from the Greek goddess Gaia).

Other adverse reactions were not reported by Tamiflu-treated patients at a markedly higher rate than those treated with placebo. Its astronomical symbol consists of a circled cross, representing a meridian and the equator; a variant puts the cross atop the circle (Unicode: ⊕ or ). 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. Earth is sometimes known as Terra in some languages, after the Roman goddess Terra. The following information (but not its interpretation) comes from Roche's "Complete Product Information" publication for Tamiflu (intended for the United States). Scientific evidence indicates that the planet formed around 4.57 billion (4.57×109) years ago, and shortly thereafter (4.533 billion years ago) acquired its single natural satellite, the Moon. 2002)[4], but was publicized only in October 2005 by a doctor who had reviewed the data (Butler 2005)[5]. It is the largest of the solar system's terrestrial planets, and the only planetary body that modern science confirms as harboring life.

The evidence for this interaction comes from a 2002 study by Roche (Hill et al. Earth is the third planet from the Sun. Probenecid was used in similar fashion during World War II to extend limited supplies of penicillin. Other: 30% (1993 est.). 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. Urban areas: 1.5%. Probenecid reduces excretion of oseltamivir's active metabolite. Forests and woodland: 32%.

It has been suggested that co-administration of oseltamivir with another drug called probenecid could dramatically extend the world's limited supply of oseltamivir. Permanent pastures: 26%. 2005). Permanent crops: 1%. (de Jong et al. Arable land: 10%. Besides allowing the infection to proceed, such incomplete suppression provides opportunities for drug resistance to develop. The land-based ecosystem depends upon topsoil and fresh water, and the oceanic ecosystem depends upon dissolved nutrients washed down from the land.

[A]t least in some patients with influenza A (H5N1) virus infection, treatment with the recommended dose of oseltamivir incompletely suppresses viral replication. Earth's biosphere produces many useful biological products, including (but far from limited to) food, wood, pharmaceuticals, oxygen, and the recycling of many organic wastes. Doctors in Vietnam concur, noting that. These ore bodies form concentrated sources for many metals and other useful elements. 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]. Mineral ore bodies have been formed in Earth's crust by the action of erosion and plate tectonics. The above treatment regimes are based upon studies of normal human influenza. These deposits are used by humans both for energy production and as feedstock for chemical production.

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. Earth's crust contains large deposits of fossil fuels: (coal, petroleum, natural gas, methane clathrate). Tamiflu is available from Roche in 75mg capsules and as a powder for aqueous suspension of 12 mg/mL. Highest point: Mount Everest 8,844 m (2005 est.). . Lowest point overall: Mariana Trench in the Pacific Ocean −10,924 m [1]. Production capacity is limited, and governments are stockpiling the drug. Lowest point on land: Dead Sea −417 m.

With increasing fears about the potential for a new influenza pandemic, oseltamivir has received substantial media attention. 42 nations and other areas are completely landlocked (see list of landlocked countries). Oseltamivir was developed by Gilead Sciences and is currently marketed by Hoffmann-La Roche (Roche) under the trade name Tamiflu®. Note: boundary situations with neighboring states prevent many countries from extending their fishing or economic zones to a full 200 nautical miles (370.4 km). Oseltamivir is a prodrug (usually administered as phosphate); it is hydrolysed hepatically to the active metabolite, the free carboxylate of oseltamivir (GS4071). Territorial sea: 12 nautical miles (22.2 km) claimed by most, but can vary. Oseltamivir was the first orally active neuraminidase inhibitor commercially developed. Exclusive economic zone: 200 nautical miles (370.4 km) claimed by most, but can vary.

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. Exclusive fishing zone: 200 nautical miles (370.4 km) claimed by most, but can vary. Oseltamivir (pronounced ah sell TAH mih veer) is an antiviral drug used in the treatment and prophylaxis of both Influenzavirus A and Influenzavirus B. Continental shelf: 200 m depth claimed by most or to depth of exploitation; others claim 200 nautical miles (370.4 km) or to the edge of the continental margin. Chimia 2004, 58, 621. Contiguous zone: 24 nautical miles (44.4 km) claimed by most, but can vary. Synthesis of Tamiflu. Note: 70.8 % of the world's surface is covered by water, 29.2 % is exposed land.

Chem. 2001, 66, 2044-2051. Water: 361.132 million km2. Org. land: 148.94 million km2. J. Total: 510.073 million km2. Synthesis of Tamiflu. 5100 to 6378 km - Inner Core.

Chem. 1998, 63, 4545-4550. 2890 to 5100 km - Outer Core. Org. 100 to 700 km - Asthenosphere. J. 35 to 2890 km - Mantle

    . (Accessed October 12, 2005, at http://www.who.int/csr/resources/publications/influenza/WHO_CDS_CSR_GIP_2005_7/en/.). 35 to 60 km - Uppermost part of mantle.

    WHO inter-country-consultation: influenza A/H5N1 in humans in Asia: Manila, Philippines, 6-7 May 2005. 0 to 35 km - Crust (locally varies between 5 and 70 km). World Health Organization. 0 to 60 km - Lithosphere (locally varies between 5 and 200 km)

      . 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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