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. Using the pull of the wind, snowkiters are able to make massive jumps and travel uphill. This argument lacks face validity, since treatment must begin before such tests results would be available anyway. The combination of kiteboarding technology with snowboarding has led to the creation of a new sport, snowkiting. 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. CRYSTAL (cookie) IS BEAUTIFUL !!!!. [22][23]. shralp! - Die aktuelle Snowboard-Wochenschau auf Deutsch.

However, sophisticated criminals could produce convincing fake packaging in the future. Effective Edge TV - Video podcast that covers all aspects of snowboarding from music, resorts, and new products. 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. Hood, HCSC has been the world's leading summer camp since 1989. The packages were labeled Generic Tamiflu. High Cascade - Located on Mt. In December 2005, 53 packages of fake Tamiflu pills were intercepted by the US Customs Service in South San Francisco. Northeast Skiing Video Podcast - Video podcast about skiing in the Northeast of the US.

This is genuinely a potential problem, but, in the face of a shortage, some individuals may be willing to face such a risk. Ridertech.com - Skiing and snowboarding video blog from the Pacific Northwest. Another argument is that it would be difficult for home users to determine whether illegally-imported Tamiflu is counterfeit. Snowflix - Your video iPod-ready weekly snow fix from the Alps. 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). Regularly updated video content that is available for download via any aggregator. 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. SNOWBOAD YA BABY.

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. On December 2, 2005, a feature film was released called "First Descent", which documented the history of the sport as well as its modern day stars. 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. Production companies work all year developing these videos. Several American states, including Massachusetts and Colorado, have issued advisories strongly discouraging this practice. Each season, many different snowboard films are released, usually in September. The short supply of Tamiflu has prompted some individuals to stockpile the drug. Snowboard videos have become a huge part of the sport.

On the other hand, at least one Democratic Senator has criticized Bush for not planning to buy enough anti-viral drugs [21]. It is almost certain that one of the origins of animosity is the average age disparity between skiiers and snowboarders. Previously, Rumsfeld has been implicated in a racketeering lawsuit involving the FDA approval of the artificial sweetner aspartame [20]. Mitigating factors may include different blind spot locations for skiiers and boarders, different riding styles and different philosphies on what snow riding is about. 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 has been much debate as to the origins of the clash. 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 culture clash has shown significant signs of diminishing as more and more snow sport enthusiasts are choosing to snowboard and more parks/resorts are allowing it.

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. There is a known culture clash between skiers and snowboarders. Some commentators (e.g., [18]) question the motives of the U.S. General safety tips for winter sports, alpine conditions and skiing should also be respected. Bush's plan included $1.4 billion for government purchases of anti-viral drugs[17]. They can be useful for the many times that a snowboard rider may wish to rest on the knees, such as after coming to a stop. 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]. For example, knee pads used for volleyball can be useful for snowboarding.

president George W. Padding can be specialized for snowboarding, or it can cross sports. In November, 2005, U.S. Padding can be useful on other body parts like hips, knees, spine and shoulders. The week before, Thai authorities said they would begin producing oseltamivir by February 2006, claiming that Roche had not patented Tamiflu in Thailand[15]. Useful safety gear includes wrist guards, padded or protected snowboard pants and a helmet. On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir[14]. The body parts most affected by injuries are the wrists, the tailbone and the head.

Roche said it would instead send all supplies to China's health ministry[13]. Wearing safety gear is highly recommended. [10][11][12] Sales were suspended in Hong Kong as well, and on November 8, also in China. As students progress in ability they can seek out specialized instruction in areas such as terrain park skills (jumps, rails, and pipes), mogul technique, off-piste riding, powder riding, and racing. 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. More advanced techniques that are taught in later lessons are linking turns, edge control, weight distribution, edge pressure, and eventually carving. 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. Other important beginner skills to learn are the falling leaf technique, side-slipping, and lift procedures.

Also in October, it was announced that Roche was in discussions with four generic drug manufacturers about possibly issuing sublicenses to increase production. Then students learn how to turn and stop with both feet in. Cipla argues that it can legally sell oseltamivir to India and 49 other less-developed countries, possibly as early as January 2006. The first lesson often begins with basic safety policies, stretching, and learning to fall, then progresses to snowboarding with one foot on the board (particularly skating and J-turns). 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. Typically, beginner snowboard lessons focus on very basic, common snowboarding skills. In October 2005, the Indian drug company Cipla announced their plan to begin manufacture of generic oseltamivir without license from Roche. The rapport developed between an instructor and a student who returns for multiple lessons is the real benefit derived from private lessons; one is taught better by a teacher who knows them, and a student is more likely to heed the advice of someone they trust.

Though significant, the quantities stockpiled would not have been sufficient to protect the entire population of these countries. Private lessons are often far more expensive than group, as it is the snowboarding analogue of being privately tutored. 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. Private lessons can be taught one-on-one or between a small group. Oseltamivir, otherwise known as Tamiflu, was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. Group lessons are often cheaper, but often have a high student-teacher ratio, resulting in less individual attention. 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. Snowboard lessons, as with ski lessons, can either be group or private lessons.

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. Professional instruction is a good way to learn proper technique, safety policies, mountain etiquette and resort rules. 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. Snowboard instruction is available at almost every ski resort from certified snowboard instructors. Other potential sources of shikimic acid include the ginko tree. For a more detailed description, see Board construction. An alternative method for production of the acid involves fermentation of genetically-modified bacteria. The various components of a snowboard are:.

Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid by means other than star anise extraction. Courses in avalanche safety are also available. The northern Vietnamese province of Lang Son has 80 km² of star anise.[7]. Avalanche equipment can be purchased or rented at outdoor equipment stores. Ninety percent of the harvest is already used by Roche in making Tamiflu. Backcountry riders are advised to take extreme caution in all conditions, to carry avalanche equipment including a probe, beacon, and shovel, and never to ride alone in the backcountry. Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 Tamiflu capsules. Snow can be extremely unstable, often leading to avalanches.

The shikimic acid is extracted from the seeds in a ten-stage manufacturing process. Safety is key when hiking and riding in the backcountry, especially after a fresh 'dump' of powder. Star anise is grown in four provinces in China and harvested between March and May. Often snowboarders use snowmobiles to make jumps into the powder. A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as at 2005). If the hill is too steep a snowmobile may not make it up the hill. 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. Snowboarders also use snowmobiles to ride in the backcountry.

(See Pandemic Fears, below). Those that don't make use of the split-board will usually strap their board to their back and hike with snowshoes. In early-2005, Roche announced a production shortage. At the top of the run, the halves are recombined, and the bindings rotated back into their sideways positions. (2004) all appeared within individual children after treatment with oseltamivir - the children did not catch the resistant strains in human-to-human transmission. When apart, the two halves can be used like cross-country skis to shuffle up the hill. It is worth noting that the oseltamivir-resistant strains detected by Kiso et al. The split-board is exactly that, a snowboard cut right down the middle.

Second, the development of a robust, resistant virus strain appears to be less likely (Ward et al., 2005). Some of those more cash-endowed riders can even hire snowcats or helicopters to take them where they want to go; this is known as catboarding or heliboarding respectively. First, these drugs work on a broader spectrum of influenza strains. Donning snowshoes or a split-board with skins, the backcountry snowboarder cuts a new path up the side of the mountain in search of the very best vistas and untouched snow. The lack of variation in neuraminidase gives two advantages to oseltamivir and zanamivir, the drugs that target that enzyme. Today, backcountry snowboarding is often for those who have enough cash to afford trips to Alaska or the mountain ranges of the West, to ride outside resorts. This means that there are relatively few variations, and there is also evidence that variations that do occur tend to be less "fit." Thus, mutations that convey resistance to oseltamivir may also tend to cripple the virus by giving it an otherwise less-functional enzyme. In fact, before snowboarding was allowed at resorts, this was the only form of snowboarding; Jake Burton, one of the original pioneers of snowboarding, never even considered resorts; backcountry was what he envisioned as the future of snowboarding.

The genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. This type of boarding started out with fresh powder-craving snowboarders who, most likely, didn't have the cash to spend at crowded upscale ski parks. Kiso et al. (2004) suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic.
. 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. The only bad part of skiing or snowboarding in powder is that if you fall, sometimes it can be very difficult to get yourself out of the very deep powder snow. 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. Powder also makes for softer landings and reduced chances of injury compared to man made terrain parks, though landing in deep snow can take some practice.

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. Powder makes for much smoother turns and in all smoother riding. They suggest that the emergence of a resistant strain may be associated with a patient's clinical deterioration. In places where almost all of the runs are groomed, and powder is a rare find, you must venture into the tree trails. (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. Generally colder climates sport the lightest, driest powder, and countries like Japan are becoming known as powder havens. de Jong et al. Even though it is hard to categorize areas in terms of powder, Powder on the east coast (USA) is generally not as common or as good as the powder on the west (USA).

She was being treated with oseltamivir at time of detection (Le et al., 2005; World Health Organization, 2005). The bad thing about powder is that is if it sits for too long it gets compacted and becomes much harder and sometimes even icy. High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. Powder is very famous for being the most fun and sometimes challenging ski and snowboarding, solely because it is so soft. 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. Powder, which occurs after a heavy snowstorm, is a specific type of snow that is very light, fluffy, and most likely deep. Second, Kiso et al. (2004) claim to have used more rigorous detection techniques than previous studies. Alpine snowboarding is significantly less popular than other kinds of snowboarding, especially in the United States.

First, children typically have a longer infection period, giving a longer time for resistance to develop. Short slalom boards with very short sidecut radii, for example, are alpine boards but can only be carved at slow speeds. Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. In fact, the only real defining characteristic of alpine snowboarding is that alpine snowboarders turn often and very hard while engaging the board in a carve. 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). A common misconception is that alpine snowboarding necessitates riding very quickly or racing. 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). (Hence riding a freestyle snowboard on groomed slopes is like riding a dirtbike on a road track or what is called SuperMoto).

Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme (Ward et al., 2005). An analogy made by some alpine enthusiasts is that freeride and freestyle snowboards are like dirt bikes, and alpine/carving snowboards are like road bikes. 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 hard plastic boots stiffens the ankle joint up significantly, making it more difficult to make small ankle adjustments while making skid turns, but making the board much more stable and powerful at higher speeds and the much higher g-forces typically felt by an alpine snowboarder in carved turns. 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. Alpine boards are usually, but not always, longer and much stiffer than freeride boards, as the particular demands of carving usually require as much usable edge length as possible. 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. They tend to angle their feet much more forward than other snowboarders, and so also ride narrower boards.

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. Alpine riders use hard plastic snowboarding boots, which resemble ski boots, except that they tend to be less stiff in the ankles and have a shortened heel, to minimize hanging over the edge of the snowboard. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. Both traditional snowboard racers (though not necessarily boardercross racers) and recreational carvers are alpine snowboarders. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. Alpine snowboarding is the practice of turning by carving the snowboard (such that the board is tracking along the edge of the board), as opposed to skidding the snowboard (where the board is traveling in a different direction than it is pointing). 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. Many ski resorts operate terrain parks which often simulate the urban skateboard environment, complete with handrails, funboxes, and machine-formed jumps.

Acidic hydrolysis then removed the imine. Freestyle snowboarding is influenced greatly by skateboarding. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. Freestyle snowboarding can be done almost anywhere that has snow. 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. Most snowboarders are thrill seekers and love to do tricks in terrain parks, which has inherent risks. 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. Freestyle is probably most demanded because of the thrill.

Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. Freestyle snowboarding is arguably the most popular discipline, and is certainly the focus of most of the lifestyle marketing in the snowboarding industry. 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. Softer boots and boards also allow riders more flexibility in body movement and the ability to reach very convoluted or stretched out, stylish body positions (known as tweaking it). 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. This is important because many freestyle snowboarders are landing switch from how they hit their jumps or their tricks, and they need to be able to ride away with ease. The corresponding epoxide is formed under basic conditions with potassium bicarbonate. Also, freestyle snowboards most likely have a true twin tip, in that the sidecut radius is equal on both sides of the board.

Reductive opening of the ketal under modified Hunter conditions (JOC 1993, 58, 6756) in dichloromethane yields an inseparable mixture of isomeric mesylates. Freestyle snowboarders typically use shorter, softer boards and softer boots than other snowboarders, as the shorter board length reduces the weight and moment of inertia, making it easier to spin and maneuver, and the softer gear makes the board more forgiving to control for the particular demands of freestyle riding, such as slower speeds, high landing impacts, quick turns, and imperfect landings. 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. spins, flips, grabs). The synthesis commences from naturally available (−)-shikimic acid. jibbing, bonking, grinding, pressing, buttering, ground spins etc.) or in the air (e.g. The reported azide-free Roche synthesis of tamiflu is summarized graphically below:. Tricks can either occur on the ground (e.g.

However, it is known that one adverse reaction added to the Japanese list was haemorrhagic Colitis (bloody diarrhoea)[6].. Freestyle snowboarding is the practice of doing different kinds of tricks on a snowboard. The authors of this section have yet to find Japan's actual listing of adverse reactions linked to oseltamivir. Many freeride purists attach an almost spiritual connotation to carving down the mountain. They did recommend adding a warning to prescription information regarding possible rashes. Freeride snowboarding, where the focus is on riding cleanly and enjoying the freedom to go and explore anywhere is influenced significantly by surfing. 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). A variant of freeriding focusing on extremely difficult lines is extreme snowboarding.

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. Freeriding is also known as all-mountain snowboarding. Roche points out that 32 million doses have been prescribed worldwide, most of them in Japan, and emphasizes the drug's safety. Most snowboarders aspire to be freeriders and will explore the mountain through trees, in powder bowls or anywhere else they feel comfortable riding. 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). Freeriding is using the natural terrain of the mountain for recreation, without focusing on technical tricks or racing. A third teen reportedly attempted to jump from the window of a building. There are four primary sub-disciplines or sub-styles within snowboarding with each favoring a slightly different snowboard design.

In February 2005, a 14-year-old male died after falling nine stories from his condominium building. For more on the history of snowboarding, see this Snowboard History Timeline. In February 2004, a 17-year-old male jumped in front of a truck and died after taking one capsule of Tamiflu. It wasn't until the mid 1980s when snowboarding exploded into the main stream when the first snowboard magazine, "Absolutely Radical", hit the racks, soon to be followed by "International Snowboard Magazine". 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 the early 1980's films by Warren Miller began to feature clips of snowboarders boosting the popularity of the sport among the skiing community. 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. Burton, Sims, Winterstick, and Avalanche snowboards originated from other parts of the country.

The number of adverse reaction reports may be a clue, but these number are not reported by Roche in this document. In the early 1980's, snowboard companies began emerging across the country. However, given that forms are voluntary, it may be difficult to determine prevalency rates or whether an actual causal relation exists. Jake Burton is the founder of Burton Snowboards, one of the largest, and most established snowboard companies in the world. Postmarketing studies are advantageous because the drug is effectively "tested" on a larger population, and previously missed adverse reactions may be discovered. The snowboard evolved from early pioneering work by people such as Sherman Poppen (who invented the "Snurfer" in his North Muskegon, Michigan home), Tom Sims, and Jake Burton. 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. These events are hosted by various winter resorts in the United States, Canada, and Europe. The following information (but not its interpretation) comes from Roche's "Complete Product Information" publication for Tamiflu (intended for the United States). Open Snowboarding Championships and the Winter X-Games. 2002)[4], but was publicized only in October 2005 by a doctor who had reviewed the data (Butler 2005)[5]. Other events that focus on snowboarding are the annual European and U.S.

The evidence for this interaction comes from a 2002 study by Roche (Hill et al. Snowboarding became a Winter Olympic Games medal-eligible sport in 1998. Probenecid was used in similar fashion during World War II to extend limited supplies of penicillin. A snowboarder's equipment consists of a snowboard, snowboarding boots, bindings to attach their boots to the board, as well as snowboarding-specific winter clothing. 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. Snowboarding is an increasingly common winter sport throughout the world where participants attach a wooden board to their feet and slide down a snow-covered mountain. Probenecid reduces excretion of oseltamivir's active metabolite. Snowboarding is a boardsport on snow similar to skiing, but inspired by surfing and skateboarding.

It has been suggested that co-administration of oseltamivir with another drug called probenecid could dramatically extend the world's limited supply of oseltamivir. This construction feature is not included in all board designs. 2005). there is also the "dgb" which is wood that goes in different directions over the core of the board to increase control. (de Jong et al. Kinking, rusting, or general dulling of the edge will significantly hinder the ability for the edge to grip the snow, so it is important that this feature is maintained. Besides allowing the infection to proceed, such incomplete suppression provides opportunities for drug resistance to develop. This sharp edge is necessary to be able to produce enough friction to ride on ice, and the radius of the edge directly affects the radius of carving turns, and in turn the responsiveness of the board.

[A]t least in some patients with influenza A (H5N1) virus infection, treatment with the recommended dose of oseltamivir incompletely suppresses viral replication. an edge: a strip of metal, tuned normally to just less than 90-degrees, that runs the length of either side of the board. Doctors in Vietnam concur, noting that. If the base becomes significantly damaged, the board may become sluggish, or if the damage is deep enough, it may even weaken the core. 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]. If the board is damaged, a new base pattern can be stone-ground into the board. The above treatment regimes are based upon studies of normal human influenza. For this reason, different base waxes are available for different snow conditions.

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. Because the base of the board comprises the bulk of the board's interaction with the snow, it is important that it be as slippery with respect to the snow as possible. Tamiflu is available from Roche in 75mg capsules and as a powder for aqueous suspension of 12 mg/mL. a base: this is the bottom of the board which is made of a graphitic material that is saturated with a wax that creates a very quick smooth, hydrophobic surface. . The properties of the core directly affect important characteristics of the board, such as flexibility and weight. Production capacity is limited, and governments are stockpiling the drug. It is typically comprised of a solid material, normally either wood, foam, or some composite plastic.

With increasing fears about the potential for a new influenza pandemic, oseltamivir has received substantial media attention. a core: the bulk of a snowboard, the core is the interior of the snowboard. 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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