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. The next time that the monkey will appear as the zodiac sign will be in the year 2016. This argument lacks face validity, since treatment must begin before such tests results would be available anyway. The Monkey is the ninth in the 12-year cycle of animals which appear in the Chinese zodiac related to the Chinese calendar. 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. Terry Pratchett makes use of this trait in his Discworld novels, in which the Librarian of the Unseen University is an orangutan who gets very violent if referred to as a monkey. [22][23]. However, pop culture often incorrectly labels apes, particularly chimpanzees, gibbons, and gorillas, as monkeys.

However, sophisticated criminals could produce convincing fake packaging in the future. The television series Monkey, the literary characters Monsieur Eek and Curious George are all examples. 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. Monkeys are prevalent in numerous books, television programs, and movies. The packages were labeled Generic Tamiflu. Calling either a simian is correct. In December 2005, 53 packages of fake Tamiflu pills were intercepted by the US Customs Service in South San Francisco. Calling apes monkeys is incorrect.

This is genuinely a potential problem, but, in the face of a shortage, some individuals may be willing to face such a risk. Note that the smallest grouping that contains them all is the Simiiformes, the simians, which also contains the apes. Another argument is that it would be difficult for home users to determine whether illegally-imported Tamiflu is counterfeit. The following lists shows where the various monkey families (bolded) are placed in the Primate classification. 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). Viktor Reinhardt, a former research veterinarian, wrote for the International Primate Protection League that: "the conditions I witnessed were so depressing that most monkeys had developed stereotypic behaviors such as pacing, rocking, bouncing, somersaulting, swaying from side to side, biting parts of their own bodies, pulling their ears, tossing their heads back and forth, or smearing feces on the cage walls." [3] [4] (mpg). 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. Use of monkeys in laboratories is highly controversial with polarizing views.

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. Highly sociable animals, monkeys are kept in many different environments. 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 the United States, around 50,000 non-human primates, most of them monkeys, have been used in experiments every year since 1973 [2] (pdf); 10,000 monkeys were used in the European Union in 2004. Several American states, including Massachusetts and Colorado, have issued advisories strongly discouraging this practice. Macaques and African green monkeys are widely used in animal testing facilities because of their relative ease of handling and their psychological and physical similarity to humans. The short supply of Tamiflu has prompted some individuals to stockpile the drug. Permits may be issued to those who qualify in the caring of monkeys.

On the other hand, at least one Democratic Senator has criticized Bush for not planning to buy enough anti-viral drugs [21]. Their legal status as pets varies in other countries. Previously, Rumsfeld has been implicated in a racketeering lawsuit involving the FDA approval of the artificial sweetner aspartame [20]. it is illegal to keep monkeys in the home; even in places where they are legal, a Department of Agriculture permit is usually required. 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. In most large metropolitan areas in the U.S. 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 monkeys may even have special needs such as diets.

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. It becomes very costly when it comes to buying food and housing them. Some commentators (e.g., [18]) question the motives of the U.S. It is not cheap to bring up a monkey. Bush's plan included $1.4 billion for government purchases of anti-viral drugs[17]. It might be bad for the monkey to place them in non-social areas which could lead to problems. 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]. Monkeys need to be placed in social areas.

president George W. It is not easy for a monkey to get used to their new environment. In November, 2005, U.S. Monkeys are known to get attached to their first owner so switching from one to another would not be a good idea. The week before, Thai authorities said they would begin producing oseltamivir by February 2006, claiming that Roche had not patented Tamiflu in Thailand[15]. While a majority of monkey owners find other homes for them, such as zoos and monkey rescues, some people report having long and rewarding relationships with monkeys. On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir[14]. They can change from one minute to the next without warning making it hard for the owner to fully understand them.

Roche said it would instead send all supplies to China's health ministry[13]. The monkeys may also become aggressive even to their owners. [10][11][12] Sales were suspended in Hong Kong as well, and on November 8, also in China. The nice looking monkey eventually has to grow up and may in most cases become wild and not easy to control. 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. Any surgical means to stem this behavior (such as removing the teeth or fingertips of the monkey) is widely considered cruel, and it is usually difficult to find veterinarians who will treat them: even exotic-animal veterinarians may not be familiar with them. 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. Most adolescent monkeys begin to bite unpredictably and pinch adults and children.

Also in October, it was announced that Roche was in discussions with four generic drug manufacturers about possibly issuing sublicenses to increase production. There needs to be a lot of time set aside for cleaning up whatever mess the monkey might make. Cipla argues that it can legally sell oseltamivir to India and 49 other less-developed countries, possibly as early as January 2006. Bored monkeys can become extremely destructive and may even go so far as to smear or throw their own feces. 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. Monkeys can not handle being away from their owners for long periods of time, such as family trips for example, due to their need of attention. In October 2005, the Indian drug company Cipla announced their plan to begin manufacture of generic oseltamivir without license from Roche. They usually require a large amount of attention.

Though significant, the quantities stockpiled would not have been sufficient to protect the entire population of these countries. They require constant supervision and mental stimulation. 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. While baby monkeys are usually as easy to keep clean as a human infant (by diapering), monkeys that have reached puberty usually remove their diapers and cannot be toilet trained. Oseltamivir, otherwise known as Tamiflu, was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. Although they may appear to be nice and friendly and can resemble human babies for some people, many people believe that monkeys should not be kept as, or seen as, pets. 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. It is rumoured that one such monkey washed up ashore and, being mistaken for a Frenchman, was hanged in Hartlepool, England this caused the people of Hartlepool to be nicknamed the monkey hangers.

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. In the Napoleonic Wars, the same practice is thought to have occurred. 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. Some were later kept in zoos, many modern captive monkeys in the UK are descended from such Victorian era monkeys. Other potential sources of shikimic acid include the ginko tree. When the British first began to explore Africa, young monkeys were often captured and taken back on board the ship to entertain sailors. An alternative method for production of the acid involves fermentation of genetically-modified bacteria. .

Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid by means other than star anise extraction. The word Moneke may have been derived from the Italian monna, which means "a female ape." The name Moneke persisted over time likely due to the popularity of Reynard the Fox. The northern Vietnamese province of Lang Son has 80 km² of star anise.[7]. In this version of the fable, a character named Moneke is the son of Martin the Ape. Ninety percent of the harvest is already used by Roche in making Tamiflu. The name monkey may come from a German version of the Reynard the Fox fable, published in around 1580. Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 Tamiflu capsules. To understand the monkeys, therefore, it is necessary to study the characteristics of the different groups individually.

The shikimic acid is extracted from the seeds in a ten-stage manufacturing process. Although both the New and Old World monkeys, like the apes, have forward facing eyes, the faces of Old World and New World monkeys look very different though again, each group shares some features such as the types of noses, cheeks and rumps. Star anise is grown in four provinces in China and harvested between March and May. Some characteristics are shared among the groups; most New World monkeys have prehensile tails while Old World monkeys do not; some have trichromatic colour vision like that of humans, others are dichromats or monochromats. A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as at 2005). Some are arboreal (living in trees), some live on the savanna; diets differ among the various species but may contain any of the following: fruit, leaves, seeds, nuts, flowers, insects, spiders, eggs and small animals. 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. Monkeys range in size from the Pygmy Marmoset, at 10 cm (4 inch) long (plus tail) and 120 g (4 oz) in weight to the male Mandrill, almost 1 metre (3 ft) long and weighing 35 kg (75 lb).

(See Pandemic Fears, below). Because they are not a single coherent group, monkeys do not have any important characteristics that they all share and are not shared with the remaining group of simians, the apes. In early-2005, Roche announced a production shortage. Also, a few monkey species have the word "ape" in their common name. (2004) all appeared within individual children after treatment with oseltamivir - the children did not catch the resistant strains in human-to-human transmission. Because of their similarity to monkeys, apes such as chimpanzees and gibbons are sometimes incorrectly called monkeys. It is worth noting that the oseltamivir-resistant strains detected by Kiso et al. These two groupings are the New World and Old World monkeys of which together there are nearly 200 species.

Second, the development of a robust, resistant virus strain appears to be less likely (Ward et al., 2005). A monkey is any member of two of the three groupings of simian primates. First, these drugs work on a broader spectrum of influenza strains. The Problem with Pet Monkeys. The lack of variation in neuraminidase gives two advantages to oseltamivir and zanamivir, the drugs that target that enzyme. Inside the monkey house at Covance, shot undercover by the British Union for the Abolition of Vivisection. 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 Impossible Housing and Handling Conditions of Monkeys in Research Laboratories", by Viktor Reinhardt, International Primate Protection League, August 2001.

The genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. Family Hominidae: humans and other great apes. Kiso et al. (2004) suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic. Family Hylobatidae: gibbons ("lesser apes"). 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. Superfamily Hominoidea

    . 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. Family Cercopithecidae: Old World monkeys.

    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. Superfamily Cercopithecoidea

      . They suggest that the emergence of a resistant strain may be associated with a patient's clinical deterioration. Catarrhini
        . (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. Family Atelidae: howler, spider and woolly monkeys. de Jong et al. Family Pitheciidae: titis, sakis and uakaris.

        She was being treated with oseltamivir at time of detection (Le et al., 2005; World Health Organization, 2005). Family Aotidae: night monkeys, owl monkeys, douroucoulis. High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. Family Cebidae: marmosets, tamarins, capuchins and squirrel monkeys. 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. Platyrrhini: New World monkeys

          . Second, Kiso et al. (2004) claim to have used more rigorous detection techniques than previous studies. Infraorder Simiiformes: simians
            .

            First, children typically have a longer infection period, giving a longer time for resistance to develop. Family Tarsiidae: tarsiers. Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. Infraorder Tarsiiformes

              . 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). Suborder Haplorrhini: tarsiers, monkeys and apes
                . 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). Suborder Strepsirrhini: non-tarsier prosimians.

                Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme (Ward et al., 2005). ORDER PRIMATES

                  . The resistance rate reported during clinical trials up to July 2004 was 0.33% in adults, 4.0% in children, and 1.26% overall. 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. 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.

                  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. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. 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. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. Mesylation, followed by removal of the solid byproduct triethylamine hydrochloride, results in an intermediate that was poised to undergo aziridination upon transimination with another equivalent of allylamine. The 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.

                  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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