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. William Norman Grigg noted the seven-branch candle holder, the "Kinara," was not used in African traditions, and suggested a symbol of Judaism was borrowed to match the seven principles of Kwanzaa.[17]. This argument lacks face validity, since treatment must begin before such tests results would be available anyway. In contrast, the African American Cultural Center considers Kwanzaa not a religious holiday, but a cultural one which does not require people to compromise their religious beliefs.[16]. 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. Some are concerned that Christians who choose to celebrate Kwanzaa are diluting their love for Christ[15]. [22][23]. Bennetta believes that Kwanzaa is ill-designed as a holiday representing African-Americans, noting that the Swahili language used in Kwanzaa is spoken in eastern Africa, while most African-Americans are descended from the people of West Africa, over 2700 miles away.[14].

However, sophisticated criminals could produce convincing fake packaging in the future. William J. 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. Black civil rights activist Reverend Jesse Lee Peterson wrote, "the whole holiday is made up! You won’t find its roots in Africa or anywhere else."[13]. The packages were labeled Generic Tamiflu. 2). In December 2005, 53 packages of fake Tamiflu pills were intercepted by the US Customs Service in South San Francisco. Others refuse to celebrate Kwanzaa because it is not a true African tradition." (Jackson, p.

This is genuinely a potential problem, but, in the face of a shortage, some individuals may be willing to face such a risk. In the book Kwanzaa (2005), author Sara McGill states, "there are many people of African descent who do not know the purpose of Kwanzaa or how to celebrate it. Another argument is that it would be difficult for home users to determine whether illegally-imported Tamiflu is counterfeit. Some criticize Kwanzaa because it is not a traditional holiday of African people, and because of its recent provenance, having been invented in 1966. 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). The origins of Kwanzaa are not secret, and are openly acknowledged by those promoting the holiday.[12]. 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. There has been criticism of Kwanzaa's authenticity and relevance, and of the motiviations of its founder, Karenga.

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. Karenga's most recent interpretation emphasizes that while every people have their various holiday traditions, all people can share in the celebration of our common humanity: "Any particular message that is good for a particular people, if it is human in its content and ethical in its grounding, speaks not just to that people, it speaks to the world."[11]. 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. In fact, it offers a clear and self-conscious option, opportunity and chance to make a proactive choice, a self-affirming and positive choice as distinct from a reactive one."[10]. Several American states, including Massachusetts and Colorado, have issued advisories strongly discouraging this practice. And it is not an alternative to people's religion or faith but a common ground of African culture...Kwanzaa is not a reaction or substitute for anything. The short supply of Tamiflu has prompted some individuals to stockpile the drug. Currently, according to the Official Kwanzaa Website authored by Karenga and maintained by Organization US, which Karenga chairs, "Kwanzaa was not created to give people an alternative to their own religion or religious holiday.

On the other hand, at least one Democratic Senator has criticized Bush for not planning to buy enough anti-viral drugs [21]. In 1997, Karenga changed his position, stating that while Kwanzaa is an African-American holiday, it can be celebrated by people of any race: "other people can and do celebrate it, just like other people participate in Cinco de Mayo besides Mexicans; Chinese New Year besides Chinese; Native American pow wows besides Native Americans."[9]. Previously, Rumsfeld has been implicated in a racketeering lawsuit involving the FDA approval of the artificial sweetner aspartame [20]. In 1977, in Kwanzaa: origin, concepts, practice, Karenga stated, that Kwanzaa "was chosen to give a Black alternative to the existing holiday and give Blacks an opportunity to celebrate themselves and history, rather than simply imitate the practice of the dominant society."[8]. 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. Bush's 2004 Presidential Message: Kwanzaa 2004, like in several previous messages, he said that during Kwanzaa, "millions of African Americans and people of African descent gather to celebrate their heritage and ancestry.". 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]). In President George W.

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. In a 2003 interview Karenga asserted that 28 million people celebrate Kwanzaa. Some commentators (e.g., [18]) question the motives of the U.S. According to a marketing survey conducted by the National Retail Foundation in 2004, Kwanzaa is celebrated by 1.6% of all Americans[7], or about 4.7 million. Bush's plan included $1.4 billion for government purchases of anti-viral drugs[17]. It is unclear how many people celebrate the holiday. 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]. To them, Kwanzaa is an opportunity to incorporate elements of their particular ethnic heritage into holiday observances and celebrations of Christmas.

president George W. Frequently, both Christmas trees and kinaras, the traditional candle holder symbolic of African-American roots, share space in kwanzaa celebrating households. In November, 2005, U.S. Today, many African-American families celebrate Kwanzaa along with Christmas and New Year's. The week before, Thai authorities said they would begin producing oseltamivir by February 2006, claiming that Roche had not patented Tamiflu in Thailand[15]. They felt that doing so would violate the principle of kujichagulia (self-determination) and thus violate the integrity of the holiday, which is partially intended as a reclamation of important African values. On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir[14]. At first, observers of Kwanzaa eschewed the mixing of the holiday or its symbols, values and practice with other holidays.

Roche said it would instead send all supplies to China's health ministry[13]. The greeting for each day of Kwanzaa is "Habari Gani"[5], Swahili words for "What's the News?" [6]. [10][11][12] Sales were suspended in Hong Kong as well, and on November 8, also in China. A model Kwanzaa ceremony is described as a ceremony which includes drumming and musical selections, libations, a reading of the "African Pledge" and the Principles of Blackness, reflection on the Pan-African colors, a discussion of the African principle of the day or a chapter in African history, a candle-lighting ritual, artistic performance, and, finally, a feast. 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. Libations are shared, generally with a common chalice, "Kikombe cha Umoja" passed around to all celebrants. 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 is customary to include children in Kwanzaa ceremonies and to give respect and gratitude to ancestors.

Also in October, it was announced that Roche was in discussions with four generic drug manufacturers about possibly issuing sublicenses to increase production. Families celebrating Kwanzaa decorate their households with objects of art, colorful African cloth, especially the wearing of the Uwole by women, and fresh fruits that represent African idealism. Cipla argues that it can legally sell oseltamivir to India and 49 other less-developed countries, possibly as early as January 2006. These principles correspond to Karenga's notion that "the seven-fold path of blackness is think black, talk black, act black, create black, buy black, vote black, and live black." [4]. 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. Each of the seven days of Kwanzaa is dedicated to one of the following principles, which are explained by Karenga as follows:. In October 2005, the Indian drug company Cipla announced their plan to begin manufacture of generic oseltamivir without license from Roche. Kwanzaa celebrates what its founder called "The Seven Principles of Kwanzaa", or Nguzo Saba (originally Nguzu Saba), which Karenga claimed "is a communitarian African philosophy" consisting of Karenga's distillation of what he deemed "the best of African thought and practice in constant exchange with the world." These seven principles comprise Kawaida, a Swahili term for tradition and reason that Karenga used to refer to his synthesized system of belief.

Though significant, the quantities stockpiled would not have been sufficient to protect the entire population of these countries. According to Karenga's 1977 Kwanzaa: Origin, Concepts, Practice, the holiday was developed "to give a Black alternative to the existing holiday and give Blacks an opportunity to celebrate themselves and history rather than simply imitate the practice of the dominant society." In 1967, a year after Karenga proposed this new holiday, he publicly espoused the view that "Jesus was psychotic" and that Christianity was a white religion that blacks should shun.[2] However, as Kwanzaa gained mainstream adherents, Karenga altered his position so as not to alienate practicing Christians, then claiming in the 1997 Kwanzaa: A Celebration of Family, Community, and Culture, "Kwanzaa was not created to give people an alternative to their own religion or religious holiday." [3]. 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. It is a celebration that has its roots in the civil rights era of the 1960s, and was established as a means to help African Americans reconnect with what Karenga characterized as their African cultural and historical heritage by uniting in meditation and study around principles that have their putative origins in what Karenga asserts are "African traditions" and "common humanist principles.". Oseltamivir, otherwise known as Tamiflu, was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. Kwanzaa is also sometimes spelled "kwaanza". 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. At the time there were seven children in Karenga's United Slaves Organization, each wanted to represent one of the letters in Kwanzaa[1] Also, the name was meant to have a letter for each of what Karenga called the "Seven Principles of Blackness".

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. An additional "a" was added to "Kwanza" so that the word would have seven letters. In addition, quinic acid, derived from the bark of the cinchona tree of Zaire, is a potential alternative base material for the production of oseltamivir. The choice of Swahili, an East African language, reflects its status as a symbol of Pan-Africanism, especially in the 1960's, though most African-Americans have West African ancestry. Other potential sources of shikimic acid include the ginko tree. The name Kwanzaa derives from the Swahili phrase "matunda ya kwanza", meaning "first fruits". An alternative method for production of the acid involves fermentation of genetically-modified bacteria. Karenga, a political activist, created Kwanzaa in California in 1966, during his leadership of the black nationalist United Slaves Organization (also known as the "US Organization").

Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid by means other than star anise extraction. . The northern Vietnamese province of Lang Son has 80 km² of star anise.[7]. Karenga calls Kwanzaa the African American branch of "first fruits" celebrations of classical African cultures. Ninety percent of the harvest is already used by Roche in making Tamiflu. It was founded by black nationalist Ron "Maulana" Karenga, and first celebrated from December 26, 1966, to January 1, 1967. Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 Tamiflu capsules. Kwanzaa consists of seven days of celebration, featuring activities such as candle-lighting and pouring of libations, and culminating in a feast and gift-giving.

The shikimic acid is extracted from the seeds in a ten-stage manufacturing process. Kwanzaa (or Kwaanza) is a week-long secular holiday honoring African-American heritage, observed from December 26 to January 1 each year, almost exclusively by African-Americans in the United States of America. Star anise is grown in four provinces in China and harvested between March and May. Hannity & Colmes (FOX News), 12/06/2005. A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as at 2005). Is Kwanzaa a Racist Holiday? By: Sean Hannity; Alan Colmes. 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. Hannity & Colmes (FOX News), 12/22/2004.

(See Pandemic Fears, below). Should African-Americans Celebrate Kwanzaa? By: Mike Gallagher; Alan Colmes. In early-2005, Roche announced a production shortage. Tolerance in the News: Kwanzaa: A threat to Christmas? By Camille Jackson | Staff Writer, Tolerance.org, 12/22/2005. (2004) all appeared within individual children after treatment with oseltamivir - the children did not catch the resistant strains in human-to-human transmission. Tavis Smiley (NPR), 12/26/2003. It is worth noting that the oseltamivir-resistant strains detected by Kiso et al. Interview: Kwanzaa creator Maulana Karenga discusses the evolution of the holiday and its meaning in 2004 By: TONY COX.

Second, the development of a robust, resistant virus strain appears to be less likely (Ward et al., 2005). Rituals of race, ceremonies of culture: Kwanzaa and the making of a Black Power holiday in the United States,1966--2000, Keith Alexander Mayes, PhD, PRINCETON UNIVERSITY, 2002. First, these drugs work on a broader spectrum of influenza strains. Brown, PhD, CORNELL UNIVERSITY, 1999. The lack of variation in neuraminidase gives two advantages to oseltamivir and zanamivir, the drugs that target that enzyme. The US Organization: African-American cultural nationalism in the era of Black Power, 1965 to the 1970s, Scot D. 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. A program to raise the faith level in African-American children through Scripture, Kwanzaa principles and culture, Janette Elizabeth Chandler Kotey, DMin, ORAL ROBERTS UNIVERSITY,1999.

The genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. URL accessed on December 20, 1999.. Kiso et al. (2004) suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic. New American. 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 True Spirit of Kwanzaa, Norman Grigg. 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. ^  Official Kwanza Website FAQ, op.cit.

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. cit. They suggest that the emergence of a resistant strain may be associated with a patient's clinical deterioration. ^  Peterson, op. (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. URL accessed on September, 2000.. de Jong et al. The Textbook League.

She was being treated with oseltamivir at time of detection (Le et al., 2005; World Health Organization, 2005). ^  The Kwanzaa Hoax, William Benetta. High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. URL accessed on December 29, 2004.. 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. FrontPage Magazine.com. Second, Kiso et al. (2004) claim to have used more rigorous detection techniques than previous studies. ^  Kwanzaa -- Racist Holiday from Hell, Reverend Jesse Lee Peterson.

First, children typically have a longer infection period, giving a longer time for resistance to develop. URL accessed on 2005-12-30.. Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. ^  The Official Kwanzaa Website - Founders Message. 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). URL accessed on 2005-12-29.. Mutant H3N2 influenza A virus isolates resistant to oseltamivir were found in 18% of a group of 50 Japanese children treated with oseltamivir (Kiso et al., 2004). ^  The Official Kwanzaa Website FAQ.

Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme (Ward et al., 2005). URL accessed on 2005-12-29.. 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 Official Kwanzaa Website. 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. URL accessed on 2005-12-29.. 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. 110, cited at Believersweb.org.

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. ^ Kwanzaa: A Celebration of Family, Community and Culture, p. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. URL accessed on 2005-12-29.. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. 21, cited at Believersweb.org. 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. ^ Kwanzaa: origin, concepts, practice, p.

Acidic hydrolysis then removed the imine. ^ "2004 Holiday Spending by Region", 'Survey by BIGresearch, conducted for National Retail Foundation', 14 October 2004. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. ^ Kwanzaa Greeting. 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. ^ A Model Kwanzaa Ceremony. 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. ^ The story of Kwanzaa.

Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. ^  [18] The Quotable Karenga, p.25, University of Sankore Press, 1967. 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. ^ Believers web. 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. Imani (Faith) To believe with all our heart in our people, our parents, our teachers, our leaders and the righteousness and victory of our struggle. The corresponding epoxide is formed under basic conditions with potassium bicarbonate. Kuumba (Creativity) To do always as much as we can, in the way we can, in order to leave our community more beautiful and beneficial than we inherited it.

Reductive opening of the ketal under modified Hunter conditions (JOC 1993, 58, 6756) in dichloromethane yields an inseparable mixture of isomeric mesylates. Nia (Purpose) To make our collective vocation the building and developing of our community in order to restore our people to their traditional greatness. 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. Ujamaa (Cooperative Economics) To build and maintain our own stores, shops and other businesses and to profit from them together. The synthesis commences from naturally available (−)-shikimic acid. Ujima (Collective Work and Responsibility) To build and maintain our community together and make our brother's and sister's problems our problems and to solve them together. The reported azide-free Roche synthesis of tamiflu is summarized graphically below:. Kujichagulia (Self-Determination) To define ourselves, name ourselves, create for ourselves and speak for ourselves.

However, it is known that one adverse reaction added to the Japanese list was haemorrhagic Colitis (bloody diarrhoea)[6].. Umoja (Unity) To strive for and maintain unity in the family, community, nation and race. The authors of this section have yet to find Japan's actual listing of adverse reactions linked to oseltamivir. They did recommend adding a warning to prescription information regarding possible rashes. The Committee stated that there was insufficient evidence to claim a causal link between oseltamivir use and the deaths of 12 Japanese children (only two from neurological problems).

On November 18, 2005, a previously-scheduled Advisory Committee to the United States Food and Drug Administration (FDA) met to reconsider the pediatric safety of Tamiflu; a six-page report was issued: Pediatric Safety Update for Tamiflu. Roche points out that 32 million doses have been prescribed worldwide, most of them in Japan, and emphasizes the drug's safety. The two deaths were reported to the Japanese health ministry by Chugai Pharmaceutical Co., a corporation half-owned by Roche, which distributes Tamiflu in Japan (Japan Times November 13, 2005; Reuters Nov 14, 2005). A third teen reportedly attempted to jump from the window of a building.

In February 2005, a 14-year-old male died after falling nine stories from his condominium building. In February 2004, a 17-year-old male jumped in front of a truck and died after taking one capsule of Tamiflu. According to Japan's Pharmaceuticals and Medical Devices Agency, there were 64 cases of psychological disorders linked to the drug between fiscal years 2000 and 2004. In May 2004, the safety division of Japan's health ministry ordered changes to the literature accompanying oseltamivir to add neurological and psychological disorders as possible side effects, including: impaired consciousness, abnormal behavior, and hallucinations.

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

Other adverse reactions were not reported by Tamiflu-treated patients at a markedly higher rate than those treated with placebo. In the clinical trials performed by Roche (comparing roughly 2,700 individuals given Tamiflu with 2,650 given placebo), nausea and vomiting were the most frequent adverse reactions reported. The following information (but not its interpretation) comes from Roche's "Complete Product Information" publication for Tamiflu (intended for the United States). 2002)[4], but was publicized only in October 2005 by a doctor who had reviewed the data (Butler 2005)[5].

The evidence for this interaction comes from a 2002 study by Roche (Hill et al. Probenecid was used in similar fashion during World War II to extend limited supplies of penicillin. 500 mg of probenecid given every six hours doubles oseltamivir's maximum blood concentration and also doubles the time that oseltamivir stays in the blood, multiplying a patient's overall exposure to the drug 2.5-fold. Probenecid reduces excretion of oseltamivir's active metabolite.

It has been suggested that co-administration of oseltamivir with another drug called probenecid could dramatically extend the world's limited supply of oseltamivir. 2005). (de Jong et al. Besides allowing the infection to proceed, such incomplete suppression provides opportunities for drug resistance to develop.

[A]t least in some patients with influenza A (H5N1) virus infection, treatment with the recommended dose of oseltamivir incompletely suppresses viral replication. Doctors in Vietnam concur, noting that. Peter Hobby (of the World Health Organization) has suggested that Vietnam should investigate and test a higher dosage and longer treatment with Tamiflu for patients with avian influenza[2][3]. The above treatment regimes are based upon studies of normal human influenza.

According to prescription information by Roche for the United States[1], Tamiflu usage is indicated for both the treatment and prophylaxis of influenza at the following dosages. Tamiflu is available from Roche in 75mg capsules and as a powder for aqueous suspension of 12 mg/mL. . Production capacity is limited, and governments are stockpiling the drug.

With increasing fears about the potential for a new influenza pandemic, oseltamivir has received substantial media attention. Oseltamivir was developed by Gilead Sciences and is currently marketed by Hoffmann-La Roche (Roche) under the trade name Tamiflu®. Oseltamivir is a prodrug (usually administered as phosphate); it is hydrolysed hepatically to the active metabolite, the free carboxylate of oseltamivir (GS4071). Oseltamivir was the first orally active neuraminidase inhibitor commercially developed.

Like zanamivir, oseltamivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells. Oseltamivir (pronounced ah sell TAH mih veer) is an antiviral drug used in the treatment and prophylaxis of both Influenzavirus A and Influenzavirus B. Chimia 2004, 58, 621. Synthesis of Tamiflu.

Chem. 2001, 66, 2044-2051. Org. J. Synthesis of Tamiflu.

Chem. 1998, 63, 4545-4550. Org. J. (Accessed October 12, 2005, at http://www.who.int/csr/resources/publications/influenza/WHO_CDS_CSR_GIP_2005_7/en/.).

WHO inter-country-consultation: influenza A/H5N1 in humans in Asia: Manila, Philippines, 6-7 May 2005. World Health Organization. PMID 15709056. J Antimicrob Chemother 2005;55(Suppl 1): i5-i21.

Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. Ward P, Small I, Smith J, Suter P, Dutkowski R. New England Journal of Medicine 2005;353(25):2633-2636. Oseltamivir Resistance - Disabling Our Influenza Defenses [Perspective].

Moscona, Anne. Nature 2005;437(7062):1108. Avian flu: Isolation of drug-resistant H5N1 virus. Le Q M, Kiso M, Someya K, Sakai Y T, Nguyen T H, Nguyen K H L, Pham N D, Ngyen H H, Yamada S, Muramoto Y, Horimoto T, Takada A, Goto H, Suzuki T, Suzuki Y, Kawaoka Y.

PMID 15337401. Lancet 2004;364(9436):759-65. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, Kimura K, et al.

(Online at: http://dmd.aspetjournals.org/cgi/content/abstract/30/1/13). Drug Metabolism and Disposition 2002;30(1):13-19. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion--correlation of in vivo and in vitro studies. Hill G, Cihlar T, Oo C, Ho E S, Prior K, Wiltshire H, Barrett J, Liu B, Ward P.

(Online at http://content.nejm.org/cgi/content/full/353/25/2667#F1). New England Journal of Medicine 2005;353(25):2667-2672. Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection. Malik; Hien, Tran Tinh; and Farrar, Jeremy.

de Jong, Menno D.; Thanh, Tran Tan; Khanh, Truong Huu; Hien, Vo Minh; Smith, Gavin J.D.; Chau, Nguyen Vinh; Cam, Bach Van; Qui, Phan Tu; Ha, Do Quang; Guan, Yi; Peiris, J.S. (Accessed on November 2, 2005, at http://www.nature.com/nature/journal/v438/n7064/full/438006a.html). Nature 2005;438(7064):6. Wartime tactic doubles power of scarce bird-flu drug [News article].

Butler, D. The New York Times (Accessed on November 5, 2005 at http://www.nytimes.com/2005/11/05/business/05tamiflu.html). Is Bird Flu Drug Really So Vexing? Debating the Difficulty of Tamiflu [News article]. Pollack, Andrew.

Fortune (Accessed on Nov 28, 2005 at http://money.cnn.com/2005/10/31/news/newsmakers/fortune_rumsfeld/?cnn=yes). Rumsfeld's growing stake in Tamiflu: Defense Secretary, ex-chairman of flu treatment rights holder, sees portfolio value growing. Oct 31, 2005. Schwartz, Nelson .

Metabolic: Aggravation of diabetes. Neurologic: Seizure, confusion. Cardiac: Arrhythmia. Digestive: Hepatitis, liver function tests abnormal.

General: Rash, swelling of face or tongue, toxic epidermal necrolysis. Safety and efficacy for prophylaxis has not been established for patients under 13 years old. Standard dosage is 75 mg once daily for patients aged 13 and older, which has been shown to be safe and effective for up to six weeks. Tamiflu is indicated for prophylaxis of influenza either during a community outbreak or following close contact with an infected individual.

Dosage for children is by weight. For influenza treatment, the standard dosage for patients 13 years and older is 75 mg twice daily for five days. Tamiflu is indicated for the treatment of influenza in patients 1 year and older who have had symptoms for no more than two days.

02-01-15 FTPPro Support FTPPro looks and feels just like Windows Explorer Contact FTPPro FTPPro Help Topics FTPPro Terms Of Use ftppro.com/1stzip.php ftppro.com/zip ftppro.com/browse2000.php PAD File Directory Business Search Directory Real Estate Database FunWebsites.org PressArchive.net WebExposure.us Google+ Directory