Oseltamivir

Oseltamivir (pronounced ah sell TAH mih veer) is an antiviral drug used in the treatment and prophylaxis of both Influenzavirus A and Influenzavirus B. Like zanamivir, oseltamivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells. Oseltamivir was the first orally active neuraminidase inhibitor commercially developed.

Oseltamivir is a prodrug (usually administered as phosphate); it is hydrolysed hepatically to the active metabolite, the free carboxylate of oseltamivir (GS4071).

Oseltamivir was developed by Gilead Sciences and is currently marketed by Hoffmann-La Roche (Roche) under the trade name Tamiflu®.

With increasing fears about the potential for a new influenza pandemic, oseltamivir has received substantial media attention. Production capacity is limited, and governments are stockpiling the drug.

Technical information

Indications and dosage

Roche recommendations in the United States

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

  • Tamiflu is indicated for the treatment of influenza in patients 1 year and older who have had symptoms for no more than two days. For influenza treatment, the standard dosage for patients 13 years and older is 75 mg twice daily for five days. Dosage for children is by weight.
  • Tamiflu is indicated for prophylaxis of influenza either during a community outbreak or following close contact with an infected individual. Standard dosage is 75 mg once daily for patients aged 13 and older, which has been shown to be safe and effective for up to six weeks. Safety and efficacy for prophylaxis has not been established for patients under 13 years old.

The above treatment regimes are based upon studies of normal human influenza.

Dosage for avian flu

Peter Hobby (of the World Health Organization) has suggested that Vietnam should investigate and test a higher dosage and longer treatment with Tamiflu for patients with avian influenza[2][3]. Doctors in Vietnam concur, noting that

[A]t least in some patients with influenza A (H5N1) virus infection, treatment with the recommended dose of oseltamivir incompletely suppresses viral replication. Besides allowing the infection to proceed, such incomplete suppression provides opportunities for drug resistance to develop. (de Jong et al. 2005)

Co-administration with probenecid

It has been suggested that co-administration of oseltamivir with another drug called probenecid could dramatically extend the world's limited supply of oseltamivir. Probenecid reduces excretion of oseltamivir's active metabolite. 500 mg of probenecid given every six hours doubles oseltamivir's maximum blood concentration and also doubles the time that oseltamivir stays in the blood, multiplying a patient's overall exposure to the drug 2.5-fold. Probenecid was used in similar fashion during World War II to extend limited supplies of penicillin. The evidence for this interaction comes from a 2002 study by Roche (Hill et al. 2002)[4], but was publicized only in October 2005 by a doctor who had reviewed the data (Butler 2005)[5].

Side effects

Information from Roche

The following information (but not its interpretation) comes from Roche's "Complete Product Information" publication for Tamiflu (intended for the United States).

In the clinical trials performed by Roche (comparing roughly 2,700 individuals given Tamiflu with 2,650 given placebo), nausea and vomiting were the most frequent adverse reactions reported. Other adverse reactions were not reported by Tamiflu-treated patients at a markedly higher rate than those treated with placebo.

According to Roche, in the postmarketing period, voluntary reports have possibly linked oseltamivir to the following other adverse reactions:

  • General: Rash, swelling of face or tongue, toxic epidermal necrolysis
  • Digestive: Hepatitis, liver function tests abnormal
  • Cardiac: Arrhythmia
  • Neurologic: Seizure, confusion
  • Metabolic: Aggravation of diabetes

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

Information from Japan: neurological effects and teen deaths

In May 2004, the safety division of Japan's health ministry ordered changes to the literature accompanying oseltamivir to add neurological and psychological disorders as possible side effects, including: impaired consciousness, abnormal behavior, and hallucinations. According to Japan's Pharmaceuticals and Medical Devices Agency, there were 64 cases of psychological disorders linked to the drug between fiscal years 2000 and 2004. In February 2004, a 17-year-old male jumped in front of a truck and died after taking one capsule of Tamiflu. In February 2005, a 14-year-old male died after falling nine stories from his condominium building. A third teen reportedly attempted to jump from the window of a building. The two deaths were reported to the Japanese health ministry by Chugai Pharmaceutical Co., a corporation half-owned by Roche, which distributes Tamiflu in Japan (Japan Times November 13, 2005; Reuters Nov 14, 2005). Roche points out that 32 million doses have been prescribed worldwide, most of them in Japan, and emphasizes the drug's safety.

On November 18, 2005, a previously-scheduled Advisory Committee to the United States Food and Drug Administration (FDA) met to reconsider the pediatric safety of Tamiflu; a six-page report was issued: Pediatric Safety Update for Tamiflu. The Committee stated that there was insufficient evidence to claim a causal link between oseltamivir use and the deaths of 12 Japanese children (only two from neurological problems). They did recommend adding a warning to prescription information regarding possible rashes.

The authors of this section have yet to find Japan's actual listing of adverse reactions linked to oseltamivir. However, it is known that one adverse reaction added to the Japanese list was haemorrhagic Colitis (bloody diarrhoea)[6].

Chemical synthesis

The reported azide-free Roche synthesis of tamiflu is summarized graphically below:

The synthesis commences from naturally available (−)-shikimic acid. The 3,4-pentylidene acetal mesylate is prepared in three steps: esterification with ethanol and thionyl chloride; ketalization with para-toluenesulfonic acid and 3-pentanone; and mesylation with triethylamine and methanesulfonyl chloride. Reductive opening of the ketal under modified Hunter conditions (JOC 1993, 58, 6756) in dichloromethane yields an inseparable mixture of isomeric mesylates. The corresponding epoxide is formed under basic conditions with potassium bicarbonate. Using the inexpensive Lewis acid magnesium bromide diethyl etherate (commonly prepared fresh by the addition of magnesium turnings to 1,2-dibromoethane in benzene:diethyl ether), the epoxide is opened with allyl amine to yield the corresponding 1,2-amino alcohol. The water-immiscible solvents methyl tert-butyl ether and acetonitrile are used to simplify the workup procedure, which involved stirring with 1 M aqueous ammonium sulfate. Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. The aminoalcohol was converted directly to the corresponding allyl-diamine in an interesting cascade sequence that commences with the unselective imination of benzaldehyde with azeotropic water removal in methyl tert-butyl ether. Mesylation, followed by removal of the solid byproduct triethylamine hydrochloride, results in an intermediate that was poised to undergo aziridination upon transimination with another equivalent of allylamine. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. Acidic hydrolysis then removed the imine. Selective acylation with acetic anhydride (under buffered conditions, the 5-amino group is protonated owing to a considerable difference in pKa, 4.2 vs 7.9, preventing acetylation) yields the desired N-acetylated product in crystalline form upon extractive workup. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. It is noted that the synthesis avoids the use of potentially explosive azide reagents and intermediates; however, the synthesis actually used by Roche uses azides. Roche has other routes to Tamiflu that do not involve the use of (−)-shikimic acid as a chiral pool starting material, such as a Diels-Alder route involving furan and ethyl acrylate or an isophthalic acid route, which involves catalytic hydrogenation and enzymatic desymmetrization.

Resistance

As with other antivirals, resistance to the agent was expected with widespread use of oseltamivir, though the emergence of resistant viruses was expected to be less frequent than with amantadine or rimantadine. The resistance rate reported during clinical trials up to July 2004 was 0.33% in adults, 4.0% in children, and 1.26% overall. Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme (Ward et al., 2005).

Mutant H3N2 influenza A virus isolates resistant to oseltamivir were found in 18% of a group of 50 Japanese children treated with oseltamivir (Kiso et al., 2004). This rate was similar to another study where resistant isolates of H1N1 influenza virus were found in 16.3% of another cohort of Japanese children (Ward et al., 2005). Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. First, children typically have a longer infection period, giving a longer time for resistance to develop. Second, Kiso et al. (2004) claim to have used more rigorous detection techniques than previous studies. Third, the dosage regimen in Japan is different from that of other nations, and some children may have been given a suboptimal dosage of oseltamivir.

High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. She was being treated with oseltamivir at time of detection (Le et al., 2005; World Health Organization, 2005).

de Jong et al. (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. They suggest that the emergence of a resistant strain may be associated with a patient's clinical deterioration. They also note that the recommended dosage of oseltamivir does not always completely suppress viral replication, a situation that could favor the emergence of resistant strains. Moscona (2005) gives a good overview of the resistance issue, and says that personal stockpiles of Tamiflu could lead to under-dosage and thus the emergence of resistant strains of H5N1.

Resistance is of concern in the scenario of an influenza pandemic, since resistance is more likely to develop due to the potentially longer duration of infection by novel viruses. Kiso et al. (2004) suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic.

The genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. This means that there are relatively few variations, and there is also evidence that variations that do occur tend to be less "fit." Thus, mutations that convey resistance to oseltamivir may also tend to cripple the virus by giving it an otherwise less-functional enzyme. The lack of variation in neuraminidase gives two advantages to oseltamivir and zanamivir, the drugs that target that enzyme. First, these drugs work on a broader spectrum of influenza strains. Second, the development of a robust, resistant virus strain appears to be less likely (Ward et al., 2005). It is worth noting that the oseltamivir-resistant strains detected by Kiso et al. (2004) all appeared within individual children after treatment with oseltamivir - the children did not catch the resistant strains in human-to-human transmission.

Production shortage/shikimic acid

In early-2005, Roche announced a production shortage. (See Pandemic Fears, below). According to Roche, the major bottleneck in oseltamivir production is the availability of shikimic acid, which cannot be economically synthesized and is only effectively isolated from Chinese star anise, an ancient cooking spice; although most autotrophic organisms produce shikimic acid, the isolation yield is low. A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as at 2005). Star anise is grown in four provinces in China and harvested between March and May. The shikimic acid is extracted from the seeds in a ten-stage manufacturing process. Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 Tamiflu capsules. Ninety percent of the harvest is already used by Roche in making Tamiflu.

The northern Vietnamese province of Lang Son has 80 km² of star anise.[7]

Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid by means other than star anise extraction. An alternative method for production of the acid involves fermentation of genetically-modified bacteria. Other potential sources of shikimic acid include the ginko tree. In addition, quinic acid, derived from the bark of the cinchona tree of Zaire, is a potential alternative base material for the production of oseltamivir.

Other actions

Tamiflu appears to be active against canine parvovirus, feline panleukopenia, the canine respiratory complex known as "kennel cough," and the emerging disease dubbed "canine flu", an equine virus that began affecting dogs in 2005. Veterinary investigation of its use for canine parvo [8] and canine flu [9]is ongoing, but many shelters and rescue groups have reported great success employing Tamiflu in the early stages of these illnesses.

Pandemic fears

Oseltamivir, otherwise known as Tamiflu, was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. In response to the epidemic, various governments – including those of the United Kingdom, Canada, United States and Australia – stockpiled quantities of oseltamivir in preparation for a possible pandemic. Though significant, the quantities stockpiled would not have been sufficient to protect the entire population of these countries.

Wikinews has news related to this article: Taiwan to violate Tamiflu patent in order to compensate for vaccine shortage

In October 2005, the Indian drug company Cipla announced their plan to begin manufacture of generic oseltamivir without license from Roche. Most patent laws allow governments to authorize supply from generic companies, subject to remuneration to patent owners to address public health problems, including emergencies, although Roche has annouced its intention to remain the sole supplier of the drug. Cipla argues that it can legally sell oseltamivir to India and 49 other less-developed countries, possibly as early as January 2006. Also in October, it was announced that Roche was in discussions with four generic drug manufacturers about possibly issuing sublicenses to increase production.

In late-October 2005, Roche announced that it was suspending shipments to pharmacies in the United States and Canada until the North American seasonal flu outbreak began, to address concerns about private stockpiling and to preserve supplies for seasonal influenza. It said that, when distribution resumes in Canada, the remaining available drug will be saved for use in high-risk settings like long-term care facilities and hospitals. [10][11][12] Sales were suspended in Hong Kong as well, and on November 8, also in China. Roche said it would instead send all supplies to China's health ministry[13].

On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir[14]. The week before, Thai authorities said they would begin producing oseltamivir by February 2006, claiming that Roche had not patented Tamiflu in Thailand[15].

U.S. Government policy and oseltamivir

In November, 2005, U.S. president George W. Bush requested Congress to fund $7.1 billion in emergency spending for flu pandemic prepardness (the Senate had already passed an $8.1 billion bill)[16]. Bush's plan included $1.4 billion for government purchases of anti-viral drugs[17].

Some commentators (e.g., [18]) question the motives of the U.S. government's endorsement and planned purchase of oseltamivir, noting Secretary of State Donald Rumsfeld's close ties to Gilead Sciences, rightsholder to the Tamiflu patent. Rumsfeld is a former chairman of Gilead, and federal disclosure forms indicate that he owns between $5 million and $25 million in Gilead stock (Schwartz 2005 [19]). The rise in Gilead's share prices from $35 to $57 per share will have added between $2.5 million to $15.5 million to Rumsfeld's net worth. Previously, Rumsfeld has been implicated in a racketeering lawsuit involving the FDA approval of the artificial sweetner aspartame [20].

On the other hand, at least one Democratic Senator has criticized Bush for not planning to buy enough anti-viral drugs [21].

Personal stockpiling of Tamiflu

The short supply of Tamiflu has prompted some individuals to stockpile the drug. Several American states, including Massachusetts and Colorado, have issued advisories strongly discouraging this practice.

One argument against individual stockpiling is that limited drugs should be kept for more strategic or ethical deployment, that is, to hard-hit areas, to people in critical roles (e.g., healthcare and government workers), to people vulnerable to seasonal flu, or to people who actually have come down with avian influenza. Ethical arguments are sometimes made: Why should affluent people (or nations) have preferred access to antiviral medications? Illegal importation may divert the drug from poorer countries where the risk of avian influenza is actually higher.

In the New England Journal of Medicine, Moscona (2005) argues that the use of personal stockpiles of oseltamivir could result in the administration of low dosages, allowing for the development of drug-resistant virus strains. Many stockpilers will only have ten 75 mg pills (the current recommended dosage for oseltamivir), but this may be insufficient for the treatment of H5N1 (de Jong 2005).

Another argument is that it would be difficult for home users to determine whether illegally-imported Tamiflu is counterfeit. This is genuinely a potential problem, but, in the face of a shortage, some individuals may be willing to face such a risk. In December 2005, 53 packages of fake Tamiflu pills were intercepted by the US Customs Service in South San Francisco. The packages were labeled Generic Tamiflu. Roche officials know of only one instance of counterfeit Tamiflu appearing outside of the United States: incorrectly-labeled pills found in Holland, which contained only Vitamin C and lactose. However, sophisticated criminals could produce convincing fake packaging in the future. [22][23]

A fourth purported problem is that the H5N1 virus can be reliably diagnosed only in a small number of labs around the world; therefore, there is no way for home users to know whether flu-like symptoms are the result of avian flu or a more benign ailment. This argument lacks face validity, since treatment must begin before such tests results would be available anyway.

A scientist investigating avian influenza stated that he and his colleagues have personal stocks of Tamiflu.

References

  • Schwartz, Nelson . Oct 31, 2005. Rumsfeld's growing stake in Tamiflu: Defense Secretary, ex-chairman of flu treatment rights holder, sees portfolio value growing. Fortune (Accessed on Nov 28, 2005 at http://money.cnn.com/2005/10/31/news/newsmakers/fortune_rumsfeld/?cnn=yes)
  • Pollack, Andrew. Is Bird Flu Drug Really So Vexing? Debating the Difficulty of Tamiflu [News article]. The New York Times (Accessed on November 5, 2005 at http://www.nytimes.com/2005/11/05/business/05tamiflu.html)
  • Butler, D. Wartime tactic doubles power of scarce bird-flu drug [News article]. Nature 2005;438(7064):6. (Accessed on November 2, 2005, at http://www.nature.com/nature/journal/v438/n7064/full/438006a.html)
  • de Jong, Menno D.; Thanh, Tran Tan; Khanh, Truong Huu; Hien, Vo Minh; Smith, Gavin J.D.; Chau, Nguyen Vinh; Cam, Bach Van; Qui, Phan Tu; Ha, Do Quang; Guan, Yi; Peiris, J.S. Malik; Hien, Tran Tinh; and Farrar, Jeremy. Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection. New England Journal of Medicine 2005;353(25):2667-2672. (Online at http://content.nejm.org/cgi/content/full/353/25/2667#F1)
  • Hill G, Cihlar T, Oo C, Ho E S, Prior K, Wiltshire H, Barrett J, Liu B, Ward P. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion--correlation of in vivo and in vitro studies. Drug Metabolism and Disposition 2002;30(1):13-19. (Online at: http://dmd.aspetjournals.org/cgi/content/abstract/30/1/13)
  • Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, Kimura K, et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 2004;364(9436):759-65. PMID 15337401
  • Le Q M, Kiso M, Someya K, Sakai Y T, Nguyen T H, Nguyen K H L, Pham N D, Ngyen H H, Yamada S, Muramoto Y, Horimoto T, Takada A, Goto H, Suzuki T, Suzuki Y, Kawaoka Y. Avian flu: Isolation of drug-resistant H5N1 virus. Nature 2005;437(7062):1108.
  • Moscona, Anne. Oseltamivir Resistance - Disabling Our Influenza Defenses [Perspective]. New England Journal of Medicine 2005;353(25):2633-2636.
  • Ward P, Small I, Smith J, Suter P, Dutkowski R. Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother 2005;55(Suppl 1): i5-i21. PMID 15709056
  • World Health Organization. WHO inter-country-consultation: influenza A/H5N1 in humans in Asia: Manila, Philippines, 6-7 May 2005. (Accessed October 12, 2005, at http://www.who.int/csr/resources/publications/influenza/WHO_CDS_CSR_GIP_2005_7/en/.)
  • J. Org. Chem. 1998, 63, 4545-4550. Synthesis of Tamiflu.
  • J. Org. Chem. 2001, 66, 2044-2051. Synthesis of Tamiflu.
  • Chimia 2004, 58, 621.

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A scientist investigating avian influenza stated that he and his colleagues have personal stocks of Tamiflu. Today, Cancun once more lives and remains an attractive option to local and foreign tourists from all over the world. This argument lacks face validity, since treatment must begin before such tests results would be available anyway. It was estimated that Cancun will be completely ready to face the demanding vacationist wave on December 2005. 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. People from all social strata helped carry water bottles to donate money in special bank accounts that principal banks created. [22][23]. The people's response was immediate and impresionant.

However, sophisticated criminals could produce convincing fake packaging in the future. to aid people who suffered. 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. There was an exhaustive campaign by the media that featured public figures, including the President Vicente Fox, actors, musicians, etc. The packages were labeled Generic Tamiflu. American actor Mel Gibson donated an important amount of money to help the people in distress. In December 2005, 53 packages of fake Tamiflu pills were intercepted by the US Customs Service in South San Francisco. reconstruction has been possible.

This is genuinely a potential problem, but, in the face of a shortage, some individuals may be willing to face such a risk. However, thanks to the aid and support of local and state governments, the federal government, the Red Cross, and civil associations. Another argument is that it would be difficult for home users to determine whether illegally-imported Tamiflu is counterfeit. Many houses were devastated, and many jobs were lost. 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). It is estimated that after Wilma left Cancun, the local tourist industry lost over US $15 Million daily. 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. All the Airport and Harbor Operations were cancelled between October 21 to the 25 due to the worst weather conditions.

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. Thousands of local and foreign tourists were hosted in improvised refuges. 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. Once the storm left the peninsula, some of the beautiful beaches of Cancun had been washed away. Several American states, including Massachusetts and Colorado, have issued advisories strongly discouraging this practice. It has been estimated that 95% of the tourism infrastructure was seriously damaged. The short supply of Tamiflu has prompted some individuals to stockpile the drug. The devastation was almost total with many of the principal roadways from the Hotel Zone completely flooded and damaged.

On the other hand, at least one Democratic Senator has criticized Bush for not planning to buy enough anti-viral drugs [21]. At least three deaths have been reported, numerous people have disappeared, and the insured damage is estimated at between US$5 and US$8 billion. Previously, Rumsfeld has been implicated in a racketeering lawsuit involving the FDA approval of the artificial sweetner aspartame [20]. Wilma made several landfalls, with the most destructive effects felt in the Yucatán Peninsula, particularly in Cancun. 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. The hurricane began accelerating in the early morning hours of October 23, exiting the northeastern tip of the Yucatán Peninsula and entering the Gulf of Mexico as a Category 2 storm. 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]). Some portions of the Yucatán Peninsula experienced hurricane force winds for well over 24 hours.

government's endorsement and planned purchase of oseltamivir, noting Secretary of State Donald Rumsfeld's close ties to Gilead Sciences, rightsholder to the Tamiflu patent. The eye slowly drifted northward, with the center passing just to the west of Cancún, Quintana Roo. Some commentators (e.g., [18]) question the motives of the U.S. Portions of the island of Cozumel experienced the calm eye of Wilma for several hours with some blue skies and sunshine visible at times. Bush's plan included $1.4 billion for government purchases of anti-viral drugs[17]. The hurricane's eye first passed over the island of Cozumel, and then made an official landfall near Playa del Carmen in the state of Quintana Roo at around midnight on October 22 EDT with winds near 140 mph. 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]. On October 21, Hurricane Wilma made landfall on Mexico's Yucatán Peninsula as a powerful Category 4 hurricane, with winds in excess of 150 mph.

president George W. At its peak, it was the most intense tropical cyclone ever recorded in the Atlantic basin and the tenth most intense globally, with the lowest atmospheric pressure ever recorded in the Western Hemisphere of 882 millibars (26.05 inHg) at sea level, exceeding the record previously held by Hurricane Gilbert that also impacted the Peninsula of Yucatán some years ago. In November, 2005, U.S. It was also the third Category 5 hurricane of the season, beating the records set by the 1960 and 1961 seasons. The week before, Thai authorities said they would begin producing oseltamivir by February 2006, claiming that Roche had not patented Tamiflu in Thailand[15]. Wilma was the twenty-first named storm, twelfth hurricane, and sixth major hurricane of the record-breaking 2005 Atlantic hurricane season. On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir[14]. Cancún is served by Cancún International Airport.

Roche said it would instead send all supplies to China's health ministry[13]. Mayan dialects are also spoken between some workers and people born in the Yucatán peninsula. [10][11][12] Sales were suspended in Hong Kong as well, and on November 8, also in China. The main language in Cancún is Spanish, although English is widely spoken throughout the tourist areas. 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. Here and there in the hotel zone are some ancient ruins. 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. Cancún's hotel zone also has an interactive aquarium where visitors can see the marine diversity of the area, swim with dolphins and feed sharks.

Also in October, it was announced that Roche was in discussions with four generic drug manufacturers about possibly issuing sublicenses to increase production. The temperatures are typically between 26°C and 36°C (78.8°F and 96.8°F). Cipla argues that it can legally sell oseltamivir to India and 49 other less-developed countries, possibly as early as January 2006. The temperature of the city is warm, moderated by the marine breeze which circulates through its avenues. 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. International brands in Downtown area are Radisson Hacienda Cancún, Best Western Plaza Caribe, Oasis America. In October 2005, the Indian drug company Cipla announced their plan to begin manufacture of generic oseltamivir without license from Roche. There are also many clubs for all types of people, including gay clubs like Karamba or Glow, but the hotels are more accessible to all types of travelers, including some with lower rates.

Though significant, the quantities stockpiled would not have been sufficient to protect the entire population of these countries. Downtown Cancún gives us a different aspect. In response to the epidemic, various governments – including those of the United Kingdom, Canada, United States and Australia – stockpiled quantities of oseltamivir in preparation for a possible pandemic. The drinking age in Mexico is 18; while in the United States, it is 21. Oseltamivir, otherwise known as Tamiflu, was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. For just about all of these students, drinking alcohol is usually the reason why they come to Cancún. 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. Around March and April, Cancún experiences a flood of college students (usually from the United States) who travel to Cancún to party.

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. Downtown is home to less expensive places to shop like Walmart, Comercial Mexicana and Soriana, not to mention several flea markets like the one in the hotel zone. 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 hotel zone tends to be rather expensive as it is aimed at visitors and relies on the all inclusive hotels to keep them all in this area allowing prices to soar. Other potential sources of shikimic acid include the ginko tree. The hotel zone is one of the most exclusive internationally, with upmarket restaurants, bars, and the like which have catered for quite a number of the rich and famous. An alternative method for production of the acid involves fermentation of genetically-modified bacteria. Four million visitors arrive each year in an average of 190 flights daily.

Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid by means other than star anise extraction. In Cancún there are about 140 hotels with 24,000 rooms and 380 restaurants. The northern Vietnamese province of Lang Son has 80 km² of star anise.[7]. He discusses this and other issues at length on his website, http://www.cafecancun.com. Ninety percent of the harvest is already used by Roche in making Tamiflu. "You can see the bottom of the Caribbean off Cancún in satellite photographs," Siegel says. Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 Tamiflu capsules. The underground water table is beginning to show symptoms of contamination, but by the standards of most populated areas in the United States the water is still relatively clean.

The shikimic acid is extracted from the seeds in a ten-stage manufacturing process. Although approximately 75% of the city has public sewer lines, many homes rely on septic tanks. Star anise is grown in four provinces in China and harvested between March and May. Sewage treatment is another danger point, he says. A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as at 2005). There has obviously been environmental damage and the situation could deteriorate rapidly, he reports, but at present (February 2005) Cancún's main problem is a breakdown of garbage collection and disposal as a result of political conflicts that will hopefully be solved by a new administration elected February 6, 2005. 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. Although some environmentalists claim that Cancún is an environmental disaster, Siegel says that is not true.

(See Pandemic Fears, below). The city Cancun and its flourishing tourism industry were heavily damaged by Hurricane Wilma, which hit the area on October 22, 2005. In early-2005, Roche announced a production shortage. A growing number are from the rest of America and Europe. (2004) all appeared within individual children after treatment with oseltamivir - the children did not catch the resistant strains in human-to-human transmission. Most 'cancunenses' here are from Yucatán and other Mexican states. It is worth noting that the oseltamivir-resistant strains detected by Kiso et al. The city has grown rapidly over the past thirty years to become a city of approximately 750,000 residents, covering the former island and the nearby mainland.

Second, the development of a robust, resistant virus strain appears to be less likely (Ward et al., 2005). Even outlets of restaurant chains such as McDonald's and Domino's Pizza are Mexican-owned. First, these drugs work on a broader spectrum of influenza strains. They do not usually own the hotels themselves. The lack of variation in neuraminidase gives two advantages to oseltamivir and zanamivir, the drugs that target that enzyme. Some observers believe that the resort is foreign-owned because they are confused by the hotel operating companies, which are international companies that supply administration and marketing services. 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 figure is close to 100% for the mainland.

The genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. Despite initial skepticism that forced the Mexican government to finance the first eight hotels, Cancún soon attracted investors from all over the world, but approximately 70% of the Hotel Zone properties are owned by Mexicans, many of them local residents, Siegel says. Kiso et al. (2004) suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic. Siegel who was the translator of Fernando Martí's "Cancun, Fantasy of Bankers," municipal authorities have struggled to provide public services for the constant influx of people, as well as to control squatters and irregular developments, which now occupy an estimated ten to fifteen percent of the mainland area on the fringes of the city, he says. 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. Unfortunately, the original very sensible master plan was repeatedly modified and, on the mainland, often ignored. 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. Development of Cancun started in 1970 and grew rapidly in the 1980s.

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. The belief that Cancun means "nido de viboras" (nest of snakes) is modern folklore, according to according to long-time resident Jules Siegel, author of the Cancun User's Guide. They suggest that the emergence of a resistant strain may be associated with a patient's clinical deterioration. It is probable that some Yucatecan or Mexican Mayanist wrote the name as Cancu'en, which was turned into Cancún by someone at the predecessor of Fonatur, the Mexican government tourism development fund that created Cancun. (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. The romanization of Mayan words varies, but it is common to use an apostrophe to indicate a kind of glottal stop. de Jong et al. Cancuen refers to a snake totem, usually identified with Kukulcan or Quetzalcoatl (the Plumed Serpent).

She was being treated with oseltamivir at time of detection (Le et al., 2005; World Health Organization, 2005). There's also a site in Guatemala called Cancuen. High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. The earliest known reference to Cancun called it Cancuen. 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. In the case of a two-syllable word, you would only use an accent to indicate that the stress falls on the first syllable, as in López. Second, Kiso et al. (2004) claim to have used more rigorous detection techniques than previous studies. In Spanish, the accent usually falls on the second syllable.

First, children typically have a longer infection period, giving a longer time for resistance to develop. The Spanish is not really correct either. Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. This is probably a result of the fact that English-language type faces available in the early days of Cancun did not have accented characters, or the operators did not know how to access them because the keyboard codes were different from the ones they were accustomed to using. 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). Although many international publications now spell Cancun as Cancún, in the area itself it is usually Cancún in Spanish and Cancun in English. 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). On the opposite side of the island from the Caribbean Sea is Nichupte Lagoon, which is used for boat and snorkelling tours of the area.

Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme (Ward et al., 2005). A causeway was built to link Cancun to the mainland, and an international airport was built, along with what was at first a model city for workers, complete with housing, schools and medical facilities. 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 government of Mexico decided to develop a tourist resort on Cancun, which was originally financed by a USD $27 million loan from the Inter-American Development Bank. 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. In the early 1950s Cancun was an almost unpopulated and undeveloped island just off the Caribbean Sea coast of the Yucatán peninsula, home to three caretakers of a coconut plantation and small Pre-Columbian ruins of the Maya civilization. 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. The mainland downtown commercial section (Cancún City), connected to the island by two bridges, has broad avenues lined with whitewashed shops, restaurants, and hotels.

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. Cancún is divided into two parts: The narrow 23-kilometer-long (14-mile) island section (Cancún Island) is lined with modern beachfront hotels surrounded by the Bahía de Mujeres (Bay of Women), the Caribbean Sea, and the Nichupte and Bojorquez lagoons. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. The beaches are almost 100 percent limestone; the porous quality of the limestone makes for cool sand even under the intense tropical sun. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. The average temperature in Cancún is 27° C (80° F) with more than 240 days of sunshine, and rain is rare, with late August through early October being the rainy season. 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. .

Acidic hydrolysis then removed the imine. It is the municipal seat of Benito Juárez municipality and a world renowned tourist resort. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. Cancún is a coastal city in Mexico's easternmost state, Quintana Roo. 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. Wichita, Kansas, United States. 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. Miami, Florida, United States.

Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. 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. 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 corresponding epoxide is formed under basic conditions with potassium bicarbonate.

Reductive opening of the ketal under modified Hunter conditions (JOC 1993, 58, 6756) in dichloromethane yields an inseparable mixture of isomeric mesylates. 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 synthesis commences from naturally available (−)-shikimic acid. The reported azide-free Roche synthesis of tamiflu is summarized graphically below:.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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