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.

This page about tamiflu includes information from a Wikipedia article.
Additional articles about tamiflu
News stories about tamiflu
External links for tamiflu
Videos for tamiflu
Wikis about tamiflu
Discussion Groups about tamiflu
Blogs about tamiflu
Images of tamiflu

A scientist investigating avian influenza stated that he and his colleagues have personal stocks of Tamiflu. The best wrist protection is soft enough to allow normal wrist motion, but is able to absorb loads for hyper extension of the wrist. This argument lacks face validity, since treatment must begin before such tests results would be available anyway. Shorts and rigid splints could cause severe forearm fractures. 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. Be aware that wrist guards made for in-line are dangerous and not recomended. [22][23]. Snowboard-related injury accounts for 100,000 of the wrist fractures in the world each season.

However, sophisticated criminals could produce convincing fake packaging in the future. Time not money will make a skilled, safe snowboarder. 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. It is worthy of note that many of the worlds pros began on old equipment, riding on very small hills. The packages were labeled Generic Tamiflu. A professional lesson, or a day spent with a skilled friend is highly recomended. In December 2005, 53 packages of fake Tamiflu pills were intercepted by the US Customs Service in South San Francisco. Beginners should start on very gentle slopes with soft snow conditions, even if they're a good alpine skier.

This is genuinely a potential problem, but, in the face of a shortage, some individuals may be willing to face such a risk. It is highly recomended that all riders wear a helmet. Another argument is that it would be difficult for home users to determine whether illegally-imported Tamiflu is counterfeit. Necessary safety measures must be taken. 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). Beginners are in great danger during first hours of practice. 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. Injuries for snowboarders are very common, especially for upperlimb: wrist, elbows and shoulders.

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. This is obviously easier with a less biased stance, such as the "duck" stance. 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. When a rider changes direction mid-run (for example a "regular" rider leads with their left foot), they are said to be riding "switch". Several American states, including Massachusetts and Colorado, have issued advisories strongly discouraging this practice. The question of how much the bindings are angled depends on the rider's purpose and preference. The short supply of Tamiflu has prompted some individuals to stockpile the drug. However, personal preference and comfort are important with regard to this setting, so experimentation is recommended.

On the other hand, at least one Democratic Senator has criticized Bush for not planning to buy enough anti-viral drugs [21]. The usual measurement is to position the bindings so that the feet are placed just wider than shoulder width apart. Previously, Rumsfeld has been implicated in a racketeering lawsuit involving the FDA approval of the artificial sweetner aspartame [20]. Obviously, the size of the rider has much to do with proper stance width. 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. Stance width is important because it determines how the rider is balanced on the board. 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]). A good snowboarder should be equally skilled in riding both ways, even if they have a particular preference.

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. Most people have a natural stance determined by experimentation, and the two stances are roughly equally common. Some commentators (e.g., [18]) question the motives of the U.S. "Goofy" is just the opposite - the right foot leads and the left foot is at the back. Bush's plan included $1.4 billion for government purchases of anti-viral drugs[17]. A "regular" stance is one in which the rider's left foot is the front foot, while the right foot is the back foot. 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]. There are two "stances" used by snowboarders.

president George W. This is most likely to happen when the rider removes the board at the top or the bottom of a run (or while on a chairlift, which could be dangerous). In November, 2005, U.S. Nevertheless, most ski areas require the use of a "leash" that connects the snowboard to the rider's leg or boot, in case the snowboard manages to get away from its rider. The week before, Thai authorities said they would begin producing oseltamivir by February 2006, claiming that Roche had not patented Tamiflu in Thailand[15]. Furthermore it reduces the dangerous prospect of a board hurtling downhill riderless, and the rider slipping downhill on his back with no means to maintain grip on a steep slope. On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir[14]. Automatic release is not required in snowboarding, as the rider's legs are fixed in a static position and twisting of the knee joint cannot occur to the same extent.

Roche said it would instead send all supplies to China's health ministry[13]. With skis, this mechanism is designed to protect from injuries (particularly to the knee) caused by skis torn in different directions. [10][11][12] Sales were suspended in Hong Kong as well, and on November 8, also in China. Snowboard bindings, unlike ski bindings, do not automatically release upon impact or after falling over. 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. Strap-in, step-in, and hybrid bindings are used by most recreational riders and all freestyle riders. 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. There are several types of bindings.

Also in October, it was announced that Roche was in discussions with four generic drug manufacturers about possibly issuing sublicenses to increase production. The bindings are fixed to the board, and hold the booted feet in place using a variety of systems. Cipla argues that it can legally sell oseltamivir to India and 49 other less-developed countries, possibly as early as January 2006. Though bindings are not strictly part of the snowboard, they are necessary for its use. 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. Other boots, such as Sorel-style boots, may look like they would work with a snowboard, but are unsuitable for snowboarding. In October 2005, the Indian drug company Cipla announced their plan to begin manufacture of generic oseltamivir without license from Roche. Snowboard boots differ from other types of boots in that they provide internal support to transfer the rider's movements to the board.

Though significant, the quantities stockpiled would not have been sufficient to protect the entire population of these countries. Hard boots have become less common and are generally only found in more specialist stores. 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. Hard boots are very similar to ski boots and provide greater stability, increased control and quicker responsiveness on the snowboard. Oseltamivir, otherwise known as Tamiflu, was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. Generally, hard boots are used for alpine carving and racing, whereas soft boots are used in freestyle and freeride. 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. Soft boots look similar to winter boots and have a relatively comfortable, flexible feel that provides the forgiveness necessary for landing jumps and balancing on rails.

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. Snowboard boots come in two main types, soft boots and hard boots. 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 designs differ primarily in:. Other potential sources of shikimic acid include the ginko tree. The base of the board may also feature graphics, often designed to make the manufacturer recognisable in photos. An alternative method for production of the acid involves fermentation of genetically-modified bacteria. Snowboard topsheet graphics can be a highly personal statement and many riders spend many hours customizing the look of their boards.

Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid by means other than star anise extraction. The top of the board typically sports graphics designed by board makers to attract riders to their boards. The northern Vietnamese province of Lang Son has 80 km² of star anise.[7]. The edges of the base are fitted with a steel edge, just a couple millimeters square, which helps the board grab the snow when tipped up on edge. Ninety percent of the harvest is already used by Roche in making Tamiflu. The base (the side of the board that touches the snow) is covered with a plastic called p-tex, which is typically sintered to help it absorb wax, which helps it slide faster. Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 Tamiflu capsules. The front or "nose" of the board is upturned, to help the board glide over uneven snow; the back or "tail" of the board may be more or less upturned to enable backwards (switch or switchstance) riding.

The shikimic acid is extracted from the seeds in a ten-stage manufacturing process. Most snowboards are constructed of a wood core and laminated with fiberglass. Star anise is grown in four provinces in China and harvested between March and May. Snowboards come in several different styles, depending on the type of riding intended:. A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as at 2005). Many professionals still opt not to involve themselves in the Olympic event, citing dissatisfaction with rules and with the concept of Olympic Snowboarding itself. 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. Despite this rivalry, it is their establishment which finally convinces the IOC to declare snowboarding a new Olympic discipline in 1995.

(See Pandemic Fears, below). Later, the ISF (International Snowboard Federation) originated primarily due to dissatisfaction with the new ISA rules. In early-2005, Roche announced a production shortage. Due to the need for universal contest regulations, the ISA (International Snowboard Association) was founded in 1994. (2004) all appeared within individual children after treatment with oseltamivir - the children did not catch the resistant strains in human-to-human transmission. The growing popularity of the sport is reflected by the history of snowboarding as an official sport: In 1985 the first World Cup is held in Zürs, Austria. It is worth noting that the oseltamivir-resistant strains detected by Kiso et al. This opinion was well expressed in Heckler Magazine's "Declaration of Independents Snowboarding, Skateboarding and Music: An Intersection of Cultures.".

Second, the development of a robust, resistant virus strain appears to be less likely (Ward et al., 2005). Many snowboarders are disappointed with the over-commercialization and of the sport, having viewed it as a very personal expression of themselves, similar to skateboarding, art and music. First, these drugs work on a broader spectrum of influenza strains. Snowboarding is now coming to terms with its popularity. The lack of variation in neuraminidase gives two advantages to oseltamivir and zanamivir, the drugs that target that enzyme. Ski companies are now absorbing many snowboard companies, creating their own and, arguably, designing skis which directly borrow technology and design from snowboards (see shaped skis and twin skis). 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. Many ski companies reacted negatively to snowboarding during the sport's infancy.

The genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. In reaction, Transworld Snowboarding created a popular t-shirt called "Answers," which included the answers to many questions posed by skiers, including: "Yes I can stop." Many resorts did not initially allow snowboards and insisted on the use of superfluous leashes and were known to insist that riders prove their ability before being allowed on the hill. Kiso et al. (2004) suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic. Snowboarding was seen as a fad. 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. During the early years of the sport, snowboards and snowboarders were not widely respected by the ski industry and culture. 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. Nowadays there are millions of snowboarders around the world and a multi-million dollar industry trying to satisfy their needs.

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. Since its early years, the snowboard has been improved steadily and has taken the world by storm. They suggest that the emergence of a resistant strain may be associated with a patient's clinical deterioration. One of the most mentionable however is Bob patent from 1972, which he sold in 1990 to Jake Burton Carpenter, founder and owner of Burton Snowboards, today's largest manufacturer of snowboard-specific products. (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. This process included different stages and individual ideas and resulted in several patents for snowboard-like constructions. de Jong et al. The history of the snowboard starts in Utah, [1]U.S.A., where pioneers like Sherman Poppen, Dimitrije Milovich, Bob Webber, Jake Burton Carpenter, Tom Sims, Mike Olson, and Chuck Barfoot developed prototypes mainly inspired by surfboards in the 1970s.

She was being treated with oseltamivir at time of detection (Le et al., 2005; World Health Organization, 2005). . High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. A snowboard is not to be confused with a monoboard. 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. Analogous to a surfboard or skateboard for snow, snowboards are typically about a metre and a half long by about 30 centimetres wide, with metal edges and an upturned lip at each end. Second, Kiso et al. (2004) claim to have used more rigorous detection techniques than previous studies. Attached to the rider's feet with bindings, it is ridden down snow-covered slopes or dry ski slopes without the use of ski poles.

First, children typically have a longer infection period, giving a longer time for resistance to develop. A snowboard is a board ridden by a rider in the sport of snowboarding. Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. ISBN 0-393-32692-0 michaelbarnett@iinet.net.au. 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). Norton & Company. 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). W.W.

Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme (Ward et al., 2005). The Snowboard Book: A Guide for All Boarders. The resistance rate reported during clinical trials up to July 2004 was 0.33% in adults, 4.0% in children, and 1.26% overall. Hart, Lowell (1997). 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. Patent 5190311 -- Snowboard binding system. 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. U.S.

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. Patent 3900204 -- Mono-ski. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. U.S. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. Patent 3378274 -- Surf-type snow ski. 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. U.S.

Acidic hydrolysis then removed the imine. This stance is becoming increasingly popular, and is the most resilient of the three. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. Duck stance: Useful for tricks by removing the forward bias altogether, the feet are angled equally outwards such as 15° and -15°. 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. Alpine stance: Used primarily for racing, the leading foot may be anything up to 70° and the trailing foot generally 5° less. 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. Forward stance: Suitable for most purposes, the leading foot is angled roughly 21° and the trailing foot at 6°.

Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. Alpine snowboards tend to be longer and thinner with a much stiffer flex for greater edge hold and better carving performance. 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. The stiff bindings and boots give much more control over the board and allow the board to be carved much more easily than with softer bindings. 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. Extreme carvers and some Boarder Cross racers also use plate bindings. The corresponding epoxide is formed under basic conditions with potassium bicarbonate. Plate - Plate bindings are used with hardboots on Alpine or racing snowboards.

Reductive opening of the ketal under modified Hunter conditions (JOC 1993, 58, 6756) in dichloromethane yields an inseparable mixture of isomeric mesylates. This allows the rider to apply pressure and effect a "heelside" turn. The 3,4-pentylidene acetal mesylate is prepared in three steps: esterification with ethanol and thionyl chloride; ketalization with para-toluenesulfonic acid and 3-pentanone; and mesylation with triethylamine and methanesulfonyl chloride. The HyBak was originally designed by inventer Jeff Grell and built by Flite Snowboards. The synthesis commences from naturally available (−)-shikimic acid. Highback - A stiff moulded support behind the heel and up the calf area. The reported azide-free Roche synthesis of tamiflu is summarized graphically below:. In 2004, K2 released the Cinch series, a similar hybrid binding; riders slip their foot in as they would a Flow binding, however rather than webbing, the foot is held down by straps which can then be micro-adjusted for superior fit and performance.

However, it is known that one adverse reaction added to the Japanese list was haemorrhagic Colitis (bloody diarrhoea)[6].. The rider's boot is held down by a webbing that covers most of the foot. The authors of this section have yet to find Japan's actual listing of adverse reactions linked to oseltamivir. An example is the Flow binding system which is similar to a strap-in binding, except that the foot enters the binding through the back (which then clips into place) rather than the top. They did recommend adding a warning to prescription information regarding possible rashes. Hybrid - There are also proprietary binding systems that seek to combine the convenience of step-in systems with the control levels attainable with strap-ins. 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). Another problem is the formation of ice in the step-in mechanism, which may make it difficult to get in and out of the bindings.

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. While much more convenient than strap-ins, they are widely considered to be inferior because they do not provide as much of an immediate response from the rider's legs to the board. Roche points out that 32 million doses have been prescribed worldwide, most of them in Japan, and emphasizes the drug's safety. Popular (and incompatible) step-in systems include Burton, K2 Clicker, Rossignol and Switch. 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). Step-ins use a technology similar to the clipless pedals in cycling, by allowing the binding to snap and engage stiff hardware on the rider's boots. A third teen reportedly attempted to jump from the window of a building. Relative to strap-in bindings, step-in bindings use a stiffer shoe sole and boot to maintain responsiveness in compensation for the lack of over the foot restraining straps and (sometimes) lack of binding highback.

In February 2005, a 14-year-old male died after falling nine stories from his condominium building. Step-in - In response to the inconvenience of strap-in bindings, step-ins were created to make entry easier for beginners, allow for fast ski-lift to slope transition, and appeal to the rental market. In February 2004, a 17-year-old male jumped in front of a truck and died after taking one capsule of Tamiflu. Such companies as Salomon, Rossignol, Bakoda, Tech Nine, Ride, Flux and Burton have created different models of cap straps. 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. Cap Strap bindings are a recent modification that provide a very tight fit to the heel cup which makes excellent edge control. 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. Also, because there are two points of pressure, the strap locations must be adjusted for each individual rider, making it more cumbersome for rental operations.

The number of adverse reaction reports may be a clue, but these number are not reported by Roche in this document. The downside for this is they take longer to put on, usually requiring the rider to sit in the snow and bend over to adjust the straps. However, given that forms are voluntary, it may be difficult to determine prevalency rates or whether an actual causal relation exists. They can be tightly ratcheted closed for a tight fit and good rider control of the board. Postmarketing studies are advantageous because the drug is effectively "tested" on a larger population, and previously missed adverse reactions may be discovered. The foot is held onto the board with two buckle straps - one strapped across the top of the toe area, and one across the ankle area. According to Roche, in the postmarketing period, voluntary reports have possibly linked oseltamivir to the following other adverse reactions:. Strap-in - These are the earliest types of bindings, but perhaps still the most popular and technical. The rider wears a boot which has a thick but flexible sole, and padded uppers.

Other adverse reactions were not reported by Tamiflu-treated patients at a markedly higher rate than those treated with placebo. Boards designed for powder conditions exaggerate the differences even more for more floatation on the powder. 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. Freeride and alpine boards, however, have a directional shape with a wider and longer nose. The following information (but not its interpretation) comes from Roche's "Complete Product Information" publication for Tamiflu (intended for the United States). Tail/nose width - Many freestyle boards have equal nose/tail specs for equal performance either direction. 2002)[4], but was publicized only in October 2005 by a doctor who had reviewed the data (Butler 2005)[5]. There is no standard way to quantify snowboard stiffness, but novices tend to prefer softer flex, racers stiffer flex, and everyone else something in between.

The evidence for this interaction comes from a 2002 study by Roche (Hill et al. Usually a softer flex makes turning easier while a harder flex makes the board more stable at high speed. Probenecid was used in similar fashion during World War II to extend limited supplies of penicillin. Flex - The flexibility of a snowboard affects its handling and typically varies with the rider's weight. 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. Shorter sidecut radii (tighter turns) are generally used for halfpipe riding while longer sidecut radii (wider turns) are used for freeride/alpine/racing riding. Probenecid reduces excretion of oseltamivir's active metabolite. Most boards use a sidecut radius between 8-9 meters.

It has been suggested that co-administration of oseltamivir with another drug called probenecid could dramatically extend the world's limited supply of oseltamivir. The curve has a radius that might be a short as 5 meters on a child's board or as large as 17 meters on a racer's board. 2005). This curve aids turning and affects the board's handling. (de Jong et al. Sidecut - The edges of the board are symmetrically curved concavely, so that the width at the tip and tail is greater than the center. Besides allowing the infection to proceed, such incomplete suppression provides opportunities for drug resistance to develop. This is termed "toe/heel-drag" and can be cured by choosing a wider board or by adjusting the stance angle.

[A]t least in some patients with influenza A (H5N1) virus infection, treatment with the recommended dose of oseltamivir incompletely suppresses viral replication. Riders with larger feet may have problems with the toes or heels overhanging the side of the board. Doctors in Vietnam concur, noting that. Most folks ride boards in the 24-25 cm range. 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]. Alpine boards are typically 18-21 cm wide, although they can be as narrow as 15 cm. The above treatment regimes are based upon studies of normal human influenza. Freestyle boards are up to 28 cm wide, to assist with balance.

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. Width - The width is typically measured at the waist of the board, since the nose and tail width varies with the sidecut and taper. Tamiflu is available from Roche in 75mg capsules and as a powder for aqueous suspension of 12 mg/mL. Another factor riders consider when selecting a snowboard is the type of riding it will be used for, freestyle boards being shorter than all-mountain boards. . The longer the board, the more stable it is at high speed, but also a bit tougher to control. Production capacity is limited, and governments are stockpiling the drug. Rather, snowboards correspond to the weight of the rider, and a board length should be selected so the rider falls in the middle of the manufacturer's weight range for that model and size.

With increasing fears about the potential for a new influenza pandemic, oseltamivir has received substantial media attention. It is a myth that the height of the rider dictates the length of the snowboard. Oseltamivir was developed by Gilead Sciences and is currently marketed by Hoffmann-La Roche (Roche) under the trade name Tamiflu®. Most people ride boards in the 140-165 cm range. Oseltamivir is a prodrug (usually administered as phosphate); it is hydrolysed hepatically to the active metabolite, the free carboxylate of oseltamivir (GS4071). Length - Boards for children are as short as 90 centimeters; boards for racers, or "alpine" riders, are as long as 215 cm. Oseltamivir was the first orally active neuraminidase inhibitor commercially developed. Freestyle (pipe): waisted, semi-stiff, medium length, soft boots, either twin-directional or directional, light, deep sidecuts.

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. Freestyle (rails): waisted, flexible, short, soft boots, twin-directional, light. Oseltamivir (pronounced ah sell TAH mih veer) is an antiviral drug used in the treatment and prophylaxis of both Influenzavirus A and Influenzavirus B. These boards are made specifically for use in powder. Chimia 2004, 58, 621. Swallow-Tail: Generally a wider board that as a split running down it's tail, which gives it the general look of a swallow's tail. Synthesis of Tamiflu. All-Mountain: waisted, varying flexes and lengths, soft boots, sometimes slightly directional, meant to perform well as a Freeride and Freestyle board.

Chem. 2001, 66, 2044-2051. Freeride: waisted, sometimes flexible, medium to long length, soft boots, directional. Org. Racing/Alpine: long, stiff to very stiff, hard boots, slightly waisted, directional. 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.

09-04-15 FTPPro Support FTPPro looks and feels just like Windows Explorer Contact FTPPro FTPPro Help Topics FTPPro Terms Of Use ftppro.com/browse2000.php Business Search Directory Real Estate Database WebExposure.us Google+ Directory Dan Schmidt is a keyboardist, composer, songwriter, and producer.