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. Apple has promoted the iPod and iTunes brands in several successful advertising campaigns, a large number of which are part of their series of silhouette commercials. This argument lacks face validity, since treatment must begin before such tests results would be available anyway. iPod sales according to Apple's quarterly financial results:. 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. iPod sales according to Apple's yearly financial results:. [22][23]. [39].

However, sophisticated criminals could produce convincing fake packaging in the future. Sales by Hewlett-Packard made up 5% of all iPod sales. 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. In July of 2005, HP reversed its decision and announced they would stop reselling the iPod by September 2005, when existing stock were projected to be depleted. The packages were labeled Generic Tamiflu. Retailers of this model included (among others) the retail giant Wal-Mart, which included a disclaimer explaining that it would not work with its own online music service. In December 2005, 53 packages of fake Tamiflu pills were intercepted by the US Customs Service in South San Francisco. The HP models were the same as the Apple iPod except for the inclusion of an "HP" logo on the back under the Apple logo and "iPod" label They were sold as the "Apple iPod + hp".

This is genuinely a potential problem, but, in the face of a shortage, some individuals may be willing to face such a risk. On January 8, 2004, Hewlett-Packard announced that they would license the iPod from Apple to create an HP-branded digital audio player based on the iPod. Another argument is that it would be difficult for home users to determine whether illegally-imported Tamiflu is counterfeit. [38]. 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). Most recently, Apple shipped 14.04 million iPods during the quarter that ended on December 31, 2005, a 207% increase over the same quarter one year prior. 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. [37] Apple shipped 6.16 million iPods during the quarter that ended on June 25, 2005, a 616% increase over the same quarter in 2004.

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 its first quarter results of 2006, Apple reported earnings of $565 million — its highest revenue in the company's history. 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 other countries, the iPod market share is significantly lower, mostly due to high import taxes and less ubiquitous marketing, so flash memory players, or hard disk based players from competitors like Creative are dominant. Several American states, including Massachusetts and Colorado, have issued advisories strongly discouraging this practice. That is why Flash players at the beginning of 2005 account for less than half the US market share they did in 2004 (their market share decreasing from 62% in January 2004 to 29% in January 2005 [36]). The short supply of Tamiflu has prompted some individuals to stockpile the drug. Therefore, Apple succeeded in chipping away at the mainstream Flash player market in the US.

On the other hand, at least one Democratic Senator has criticized Bush for not planning to buy enough anti-viral drugs [21]. This success was especially based on the introduction of the iPod mini. Previously, Rumsfeld has been implicated in a racketeering lawsuit involving the FDA approval of the artificial sweetner aspartame [20]. Within one year from January 2004 to January 2005, its US market share tremendously increased by 34% from 31% to 65%. 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. [35] According to the latest financial statements, iPod's market share accounts for 74% in the US in July 2005. 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]). [34] The iPod currently dominates the digital audio player market in the US, frequently topping best-seller lists.

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. Fortune magazine reported on June 27, 2005 that Apple had sold over 15 million iPods, including 5.3 million in the first quarter of that year. Some commentators (e.g., [18]) question the motives of the U.S. This equates to 100 iPods sold every minute throughout the quarter. Bush's plan included $1.4 billion for government purchases of anti-viral drugs[17]. At the Macworld Expo keynote speech[33] on January 10, 2006, Apple CEO Steve Jobs reported sales of over 42 million iPods total, and 14 million in the first quarter of fiscal year 2006. 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]. Sites like iLounge and The Apple Collection have parts of their sites devoted to iPod concepts, things varying from completely touch screen iPods to iPods that include an integrated mobile phone.

president George W. iPod design is also a part of this ecosystem. In November, 2005, U.S. Along with the introduction of the nano they also introduced nano tubes (most likely a joke on nanotubes), a silicone case with no screen, dock connector, or headphone port protection, but a cover over the click wheel, and the hold switch. The week before, Thai authorities said they would begin producing oseltamivir by February 2006, claiming that Roche had not patented Tamiflu in Thailand[15]. Apple themselves even make some. On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir[14]. There are a host of different types and brands, all different for each iPod owners different needs.

Roche said it would instead send all supplies to China's health ministry[13]. Some are silicone, others are hard plastic, some you can't even reach the controls through. [10][11][12] Sales were suspended in Hong Kong as well, and on November 8, also in China. Kate Spade, iSkin, Speck, Incase, and Chums all produce these cases. 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. People buy these accessories not only to protect their iPods but also to make fashion statements. 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. Besides technological peripherals there are also cases.

Also in October, it was announced that Roche was in discussions with four generic drug manufacturers about possibly issuing sublicenses to increase production. Other companies (most notably Griffin Technology) make add-ons that allow your iPod to record your voice, charge your iPod on the go, play your tunes over the radio, or use your iPod wirelessly with a remote. Cipla argues that it can legally sell oseltamivir to India and 49 other less-developed countries, possibly as early as January 2006. Companies such as JBL, Bose, Altec Lansing, and Kensington all make speakers that are designed specifically to work with the iPod, using the iPod's thirty pin dock connector. 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. A host of different companies produce accessories that are designed to work with the iPod. In October 2005, the Indian drug company Cipla announced their plan to begin manufacture of generic oseltamivir without license from Roche. The large accessories market that has built up around the iPod is sometimes described as the iPod ecosystem.

Though significant, the quantities stockpiled would not have been sufficient to protect the entire population of these countries. Arguing that the cheap songs from iTMS have contributed significantly to the iPods' great success, record labels are also seeking a share of profits from the iPod division itself and they hope to accomplish this by putting pressure on Apple to differentiate between "hot singles" and "golden oldies." Jobs responded by accusing the record industry of being greedy [26]. 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. Aside from the controversial iPod-exclusive AAC format of audio files, SonyBMG and Warner Music who had initially signed on with Apple have lately complained that they have been undercharged for the value of their songs due to iTMS's flat fee. Oseltamivir, otherwise known as Tamiflu, was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. Steve Jobs has stated "We would like to break even (or) make a little bit of money (on the iTunes Music Store) but it's not a money maker." The role of the iTMS is not to sell songs, but rather to promote the sale of iPods by offering owners a convenient service for music. 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. Yet Realnetworks has continued to update the technology allowing iPod owners to download purchased music from RealNetworks music store.

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. For a short time in 2004, RealNetworks had advertised that tracks purchased from their RealPlayer Music Store could be played on an iPod through the use of their Harmony technology; however, an iPod update released at the time of the iPod photo launch disabled files created by Harmony. 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. Microsoft and RealNetworks have accused Apple of using iPod, the iTunes Music Store, and FairPlay to lock iPod users into using iTunes exclusively (and vice versa), creating a vertical monopoly. Other potential sources of shikimic acid include the ginko tree. No portable music player other than the iPod can play the DRM-enabled files sold on the iTMS, and the iPod cannot play files protected with other DRM technologies, such as Microsoft's DRM format or RealNetwork's Helix-DRM system. An alternative method for production of the acid involves fermentation of genetically-modified bacteria. However, the files can also be burned to CD, at which time those DRM restrictions are removed.

Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid by means other than star anise extraction. Apple encrypts the AAC audio files using the controversial FairPlay digital rights management (DRM) system, so that only authorized computers (up to five) and unlimited iPods can play them. The northern Vietnamese province of Lang Son has 80 km² of star anise.[7]. Advertised that any song was 99¢, the music bought from it can be uploaded onto the iPod and the store has become the dominant online music service, helping the sale of iPods. Ninety percent of the harvest is already used by Roche in making Tamiflu. Introduced on April 28, 2003 the iTunes Music Store (iTMS) is an online music store run by Apple and built into iTunes. Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 Tamiflu capsules. Another popular tool is vPod, a stand alone freeware tool for copying music from your PC to iPod.

The shikimic acid is extracted from the seeds in a ten-stage manufacturing process. Some of the more notable examples are the ml iPod plugin for Winamp, that allows users to manage their iPod content through Winamp, and Anapod Explorer, produced by Redchair Software, which presents a Windows Explorer-like interface for managing the content on an iPod. Star anise is grown in four provinces in China and harvested between March and May. Many of these third-party tools allows functionality not available through iTunes, such as the ability to copy music off the iPod back to the host PC. A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as at 2005). However, several third-party tools exists that addressed synchronization of the iPod. 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. Apple Computer endorses only one official method for synchronizing with the iPod: iTunes.

(See Pandemic Fears, below). Additionally, many aftermarket stereo manufacturers Kenwood, Alpine, etc, have iPod integration solutions to allow one of their head units to control and play music from an iPod. In early-2005, Roche announced a production shortage. Virtually any vehicle that has a factory CD changer controller port on the stereo can be integrated with an iPod using this kit. (2004) all appeared within individual children after treatment with oseltamivir - the children did not catch the resistant strains in human-to-human transmission. Using Peripheral Electronics' iPod2Car adaptor kit, an iPod can be thus integrated into many vehicles which wouldn't otherwise allow it. It is worth noting that the oseltamivir-resistant strains detected by Kiso et al. In 2006, this feature will also be available in other foreign cars (outside US): Japan: Lexus, Nissan, Mazda, Daihatsu, BMW, MINI, smart, and Alfa Romeo.

Second, the development of a robust, resistant virus strain appears to be less likely (Ward et al., 2005). This feature will also be available in other cars soon: Audi, Chrysler, Dodge, Ferrari, Honda, Infiniti, Jeep, Nissan, and Volkswagen. First, these drugs work on a broader spectrum of influenza strains. This feature is only available in certain cars:. The lack of variation in neuraminidase gives two advantages to oseltamivir and zanamivir, the drugs that target that enzyme. In some cars, music can be controlled through the steering wheel. 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. Not to be confused with "iPod your Car" which allows car integration on a personal car, iPod Car integration allows one to connect an iPod to a car, and listen to premade car playlists for the car, or the entire library through car speakers.

The genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. Some reviews in the arstechnica.com showed that the battery in iPod nano is soldered in the mainboard and in the 5G iPod it is more difficult to be removed and "It's actually affixed to the metal backplate and sits above its own power management circuitry and right next the headphone port and its driver circuitry". Kiso et al. (2004) suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic. The big question now is if the 5th Generation iPod battery can be replaced by users in the same manner as the other generations of iPod. 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. These batteries often contain more capacity than the standard Apple batteries. 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. As a response to the battery problem, multiple 3rd parties [23] [24] [25] have appeared that are selling iPod battery replacement kits for one third of the price that Apple charges customers for a battery replacement.

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. [22]. They suggest that the emergence of a resistant strain may be associated with a patient's clinical deterioration. Some iPod users also defended Apple by pointing out that their iPods had lasted longer than 18 months, while other viewers suggested that the brothers had attacked Apple solely for the sake of publicity. (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. The movie depicted the Brothers vandalizing Apple ads in the New York City area with graffiti proclaiming that "iPod's unreplaceable battery lasts only 18 months." [21] The movie was widely linked and viewed, with much of the commentary failing to mention Apple's recent change in policy. de Jong et al. The movie, called iPod's Dirty Secret, apparently made before the change in policy, expressed anger because the battery on their early model iPod had failed after eighteen months and Apple refused to replace it.

She was being treated with oseltamivir at time of detection (Le et al., 2005; World Health Organization, 2005). On November 21, 2003, a short film produced by iPod owners The Neistat Brothers was released on the Internet. High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. [20]. 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. On November 14, 2003, Apple quietly announced a battery replacement program that initially cost $99 [19] (now $59), and one week later offered users the option to extend the warranty of their iPods for $59. Second, Kiso et al. (2004) claim to have used more rigorous detection techniques than previous studies. This situation led to a small market for third-party battery replacement kits.

First, children typically have a longer infection period, giving a longer time for resistance to develop. The official policy was that the customer should buy a refurbished replacement iPod, at a cost almost equivalent to a brand new iPod. Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. Compounding this problem, Apple would not replace worn-out batteries either. 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). This is unusually difficult for a consumer device, but at least half a dozen well-known rivals to the iPod have a similarly enclosed battery. Mutant H3N2 influenza A virus isolates resistant to oseltamivir were found in 18% of a group of 50 Japanese children treated with oseltamivir (Kiso et al., 2004). The battery in all iPod models cannot be removed or replaced by the user without levering the unit open.

Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme (Ward et al., 2005). Apple has published guidelines on its web site for maximizing the life of an iPod battery. The resistance rate reported during clinical trials up to July 2004 was 0.33% in adults, 4.0% in children, and 1.26% overall. In other words, the battery will continue to have a useful life through the equivalent of five hundred complete discharges and recharges; through time and use, the life of the battery will generally decrease until eventually it is not able to power the iPod for more than a few minutes. 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. Like most lithium-based batteries, the iPod battery lasts roughly 500 full recharge cycles. 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. Apple designed the iPod with an internal lithium ion battery that users cannot easily replace (the first and second generation iPods used lithium polymer batteries).

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 nano originally wasn't shipped with these, but after the complaints Apple started bundling them with no price change. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. For this reason Apple has started packaging both the nano and the 5th Generation iPod with cloth carrying cases which help to prevent scratches to the screen and body, both the plastic front and metal back, but do not provide unfettered access to the screen or controls. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. There have been a number of complaints about the Nano's screen being too soft, resulting in it becoming easily scratched or even broken if put under any strain. 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. The iPod nano is available in white and black, in both 2 GB (US$199) and 4 GB (US$249) configurations.

Acidic hydrolysis then removed the imine. The click wheel is used to input the digits to the passcode. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. The screenlock option lets users set a 4 digit passcode for their iPod, and once the screenlock is activated the only buttons that can be pressed are the skip forwards and backwards and the play/pause buttons. 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 nano saves the user's stopwatch stats for multiple timing sessions, which is useful for comparing times. 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. While the timer is on, the Start button changes to a Lap button that allows the user to time individual laps.

Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. The stopwatch feature allows users to press Start to start the timer, and the Stop button to stop. The water-immiscible solvents methyl tert-butyl ether and acetonitrile are used to simplify the workup procedure, which involved stirring with 1 M aqueous ammonium sulfate. The clocks can be set to adjust for Daylight Saving Time. 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 world clock allows users to set the time in cities around the world, and set alarms for each time zone. The corresponding epoxide is formed under basic conditions with potassium bicarbonate. These features were new to the iPod operating system, including the addition of world clocks, a stopwatch, and a screenlock option.

Reductive opening of the ketal under modified Hunter conditions (JOC 1993, 58, 6756) in dichloromethane yields an inseparable mixture of isomeric mesylates. The iPod nano has several features that would later be included into the fifth generation iPod. 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 nano is the first dock connector iPod that cannot sync to any PC (Windows or Mac) via FireWire cable, though it can still be charged via a Firewire connection. The synthesis commences from naturally available (−)-shikimic acid. It retains the standard 30-pin dock connector for compatibility with third-party peripherals. The reported azide-free Roche synthesis of tamiflu is summarized graphically below:. The headphone jack is located on the bottom.

However, it is known that one adverse reaction added to the Japanese list was haemorrhagic Colitis (bloody diarrhoea)[6].. It has a 65,536 color display that can show photographs, and connects to a computer via USB 2.0. The authors of this section have yet to find Japan's actual listing of adverse reactions linked to oseltamivir. Based on flash memory instead of a hard drive, the iPod nano is 0.27 inches (6.9 millimeters) thick, weighs 1.5 ounces (42 grams), and is 62% smaller by volume than its predecessor. They did recommend adding a warning to prescription information regarding possible rashes. On September 7, 2005, Apple announced the successor to the iPod mini, the iPod nano. 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). or 22 g) and approximates in size to a pack of chewing gum (originally, the iPod shuffle website contained a footnote advising people not to eat the iPod shuffle like gum; it was later removed, possibly because several users photographed themselves with their iPod shuffles in their mouths.) Like the rest of the iPod family, iPod shuffle can operate as a USB mass storage device.

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 iPod shuffle weighs less than one ounce (0.78 oz. Roche points out that 32 million doses have been prescribed worldwide, most of them in Japan, and emphasizes the drug's safety. Users can set iTunes to fill iPod shuffle with a random selection from their music library each time the device connects to the computer. 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). The iPod shuffle has no screen and therefore has limited options for navigating between music tracks: users can play songs either in the order set in iTunes or in a random (shuffled) order. A third teen reportedly attempted to jump from the window of a building. One review regards it as having one of the best-sounding audio systems of all the iPod models.

In February 2005, a 14-year-old male died after falling nine stories from his condominium building. The shuffle has a SigmaTel processor. In February 2004, a 17-year-old male jumped in front of a truck and died after taking one capsule of Tamiflu. Unlike other iPod models, iPod shuffle cannot play Apple Lossless or AIFF encoded audio files—possibly due to the iPod shuffle's smaller processing power. 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. The shuffle comes in two models: 512 MB (up to 120 4-minute songs encoded at 128 kbit/s) and 1 GB (up to 240). 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. iPod shuffle introduced flash memory (rather than a hard drive) to iPods for the first time.

The number of adverse reaction reports may be a clue, but these number are not reported by Roche in this document. Apple announced iPod shuffle at Macworld Expo on January 11, 2005 with the taglines "Life is random" and "Give chance a chance". However, given that forms are voluntary, it may be difficult to determine prevalency rates or whether an actual causal relation exists. With the introduction of the iPod nano, the iPod mini was discontinued. Postmarketing studies are advantageous because the drug is effectively "tested" on a larger population, and previously missed adverse reactions may be discovered. Also, the second generation iPod minis did not include the AC adapter or the FireWire cable bundled with previous models. According to Roche, in the postmarketing period, voluntary reports have possibly linked oseltamivir to the following other adverse reactions:. In addition, they featured richer case colors (though Apple discontinued the gold color) and other minor aesthetic changes (the color of the lettering on the click wheel now matched the color of the iPod mini).

Other adverse reactions were not reported by Tamiflu-treated patients at a markedly higher rate than those treated with placebo. Most notably, both models featured an increased battery life of up to 18 hours. 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. In February 2005, the second-generation [18] iPod mini came on the market with a new 6 GB model at $249 and an updated 4 GB model priced at $199. The following information (but not its interpretation) comes from Roche's "Complete Product Information" publication for Tamiflu (intended for the United States). Silver models sold best, followed by blue ones, while the least popular was the gold. 2002)[4], but was publicized only in October 2005 by a doctor who had reviewed the data (Butler 2005)[5]. Apple initially made iPod mini devices available in five colors: silver, gold, blue, pink, and green.

The evidence for this interaction comes from a 2002 study by Roche (Hill et al. The center button still acted as a select button. Probenecid was used in similar fashion during World War II to extend limited supplies of penicillin. iPod mini introduced the popular "click wheel" that was incorporated into later iPods: the touch-sensitive wheel means that users can move a finger around it to highlight selections on the screen, while the unit's Menu, Back, Forward, and Play/Pause buttons are part of the wheel itself, letting a user press down on part of the wheel to activate one of those functions. 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. Critics panned it as too expensive, but it proved to be overwhelmingly popular, and Apple Stores had difficulty keeping the model in stock. Probenecid reduces excretion of oseltamivir's active metabolite. It had 4 GB of storage and a price of $249 (at the time, only $50 below the 15 GB third-generation iPod).

It has been suggested that co-administration of oseltamivir with another drug called probenecid could dramatically extend the world's limited supply of oseltamivir. On January 6, 2004, Apple introduced the first iPod mini. 2005). The iPod mini was discontinued on September 7, 2005 after Apple announced it was to be replaced by the iPod nano, which was 62% smaller in size and included a color screen. (de Jong et al. iPod minis used Microdrive hard drives for storage. Besides allowing the infection to proceed, such incomplete suppression provides opportunities for drug resistance to develop. Its smaller display had one less line than previous models, limiting the on-screen track identification to title and artist only, and not the album.

[A]t least in some patients with influenza A (H5N1) virus infection, treatment with the recommended dose of oseltamivir incompletely suppresses viral replication. The iPod mini had largely the same feature set as the full-sized iPod, but lacked support for some third-party accessories. Doctors in Vietnam concur, noting that. Apple entered the market for "mini"-form-factor digital audio players in January 2004, with the introduction of the iPod mini, competing directly with players like Creative's Zen Micro and Digital Networks Rio Carbon. 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 price point remains the same as the fourth-generation model. The above treatment regimes are based upon studies of normal human influenza. The capacity of the iPod was increased to 30 GB from the previous 20 GB.

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. The new Harry Potter iPod retains the laser engraved Hogwarts crest on back of the device and is sold with the "complete Harry Potter" (the first 6 books in the Harry Potter series). Tamiflu is available from Roche in 75mg capsules and as a powder for aqueous suspension of 12 mg/mL. On October 12, 2005 Apple reintroduced the Harry Potter collectible iPod along with the update of the iPod line. . A third-party addon will still be required in order to record audio on the iPod, as it was in previous generations. Production capacity is limited, and governments are stockpiling the drug. Other notable improvements include the reduction of minor audio defects, such as hard drive noise being heard through the headphone jack, as well as an increase in recording quality to 44.1 kHz stereo, 22.05 kHz mono.

With increasing fears about the potential for a new influenza pandemic, oseltamivir has received substantial media attention. The fifth-generation iPod no longer supports file transfers via FireWire, but still supports charging using FireWire. Oseltamivir was developed by Gilead Sciences and is currently marketed by Hoffmann-La Roche (Roche) under the trade name Tamiflu®. One must purchase one separately in order to charge it from the AC. Oseltamivir is a prodrug (usually administered as phosphate); it is hydrolysed hepatically to the active metabolite, the free carboxylate of oseltamivir (GS4071). Apple has also discontinued the inclusion of an AC adapter and FireWire cable. Oseltamivir was the first orally active neuraminidase inhibitor commercially developed. The fifth-generation iPod also comes with a thin slip case, most likely in response to many complaints concerning the iPod nano's easily scratchable surface.

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. In addition, the earphones plug is smaller. 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 the iPod nano, it comes in two colors, white and black, and it features the World Clock, Stopwatch, and Screen Lock applications. Chimia 2004, 58, 621. Griffin has, however, released a new version of the iTrip for the new iPod, which mounts to the dock connector on the bottom of the unit. Synthesis of Tamiflu. Gone from the fifth-generation iPod is the remote control accessory port, previously found beside the headphone port, meaning that accessories such as the Griffin iTrip will no longer work.

Chem. 2001, 66, 2044-2051. The headphone jack has been moved from the center of the top to the right of the top, while the hold switch has been moved to the left side of the top. Org. Apple has stopped using the click wheels used in the fourth generation iPod and iPod mini from their previous supplier, Synaptics Inc of San Jose, CA, and now uses an in-house solution. J. The new click wheel is completely flat, unlike older models where the center button is slightly rounded. Synthesis of Tamiflu. The click wheel design is the same as the previous generation, but is marginally smaller than before.

Chem. 1998, 63, 4545-4550. Watching movies reduces that amount to 2 and 3 hours respectively. Org. The reported battery life for the 30 GB is 14 hours and for the 60 GB is around 20 hours. J. It is also 30% thinner than the previous full-size iPod. (Accessed October 12, 2005, at http://www.who.int/csr/resources/publications/influenza/WHO_CDS_CSR_GIP_2005_7/en/.). The screen size is now 2.5" (6.35 cm) diagonally, 0.5" larger than the previous iPod.

WHO inter-country-consultation: influenza A/H5N1 in humans in Asia: Manila, Philippines, 6-7 May 2005. It can also display video on an external TV using the iPod AV or S-video cables with the iPod Universal Dock [17], however video watched on a TV is often of poor quality due to the fact that iPod video can only play videos up to 480x480. World Health Organization. It has a 65,536 color (16-bit) screen, [15] with a 320 x 240 QVGA transflective TFT display, and is able to display video on an external TV via the AV cable accessory [16], which plugs into the headphone minijack and splits into composite video and audio output connectors with RCA jacks. PMID 15709056. However, the 30 and 60 GB versions differ in body thickness, the 30 GB version being slightly thinner. J Antimicrob Chemother 2005;55(Suppl 1): i5-i21. On October 12, 2005, Apple announced at the "One more thing..." [14] event, the fifth-generation iPod, which featured the ability to play MPEG-4 and H.264 video with resolutions of up to 480 x 480 (maximum pixel count of 230,400) and 320 x 240 (maximum pixel count of 76,800), respectively (videos purchased from the iTunes Music Store are limited to 320 x 240.) Some users have reported the ability to play widescreen resolutions up to 640x360 using MPEG-4 and 400x192 using H.264 (total pixel count is equal to the stated maximums) The new models are available in 30 and 60 GB capacities and are priced the same as the previous generation at $299 and $399 USD, respectively.

Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. The only way to get a Harry Potter Collector's iPod is to buy it online [13] along with the complete set of Harry Potter audiobooks, at a combined price (as of October 25, 2005) of $548 USD. Ward P, Small I, Smith J, Suter P, Dutkowski R. The iPod was launched along with the Harry Potter audiobooks on the iTunes Music Store. New England Journal of Medicine 2005;353(25):2633-2636. [12]. Oseltamivir Resistance - Disabling Our Influenza Defenses [Perspective]. This model was superseded on October 12, 2005 with a fifth generation Harry Potter 30 GB Collector's iPod.

Moscona, Anne. On September 7, 2005, Apple released a limited-edition Harry Potter fourth-generation 20 GB iPod that featured a laser engraved Hogwarts crest on the back. Nature 2005;437(7062):1108. The U2 iPod was the last iPod to ship with Firewire connection cables and firmware, prompting some analysts to speculate about the future inclusion of Firewire interfaces on Apple products. Avian flu: Isolation of drug-resistant H5N1 virus. On October 12, 2005, Apple discontinued the iPod U2 Special Edition with the introduction of the fifth-generation iPod. 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. On June 28, 2005, at the same time as the announcement of the merger of the iPod and the iPod photo lines, Apple added a color screen and photo capabilities to the iPod U2 Special Edition while dropping the price to $329.

PMID 15337401. [11]. Lancet 2004;364(9436):759-65. It also included an iTunes Music Store coupon redeemable for $50 off of the price of The Complete U2, a "digital boxed set" featuring over 400 tracks of U2 music. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Originally retailing for $349, it had a black front with a red click wheel (the colors of U2's latest album, How to Dismantle an Atomic Bomb), and featured the signatures of U2's band members engraved on the back. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, Kimura K, et al. On October 28, 2004, Apple released a black-and-red edition of the fourth-generation iPod called iPod U2 Special Edition.

(Online at: http://dmd.aspetjournals.org/cgi/content/abstract/30/1/13). To fix this problem, a small piece of cellophane wrap with a hole in it or a thin, non-conductive washer may be placed between the headphone jack and the plug. Drug Metabolism and Disposition 2002;30(1):13-19. The likely cause for this malfunction is that a small metal disk on the base of the earphone plugs makes electrical contact with the metallic back of iPod, tripping the detection mechanism. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion--correlation of in vivo and in vitro studies. This erroneous detection occurs with some third-party headphones (such as Sennheiser models), but users have also reported experiencing the problem with the supplied Apple earbuds. Hill G, Cihlar T, Oo C, Ho E S, Prior K, Wiltshire H, Barrett J, Liu B, Ward P. A headphone contact switch, in coordination with iPod's auto-pause feature, is supposed to pause the music playback if the headphones are disconnected, but incorrectly detects that the headphones have been removed.

(Online at http://content.nejm.org/cgi/content/full/353/25/2667#F1). These iPods have a glitch that causes them to pause on their own, despite the hold switch being activated. New England Journal of Medicine 2005;353(25):2667-2672. Popular optional accessories included the dock, a FireWire cable (which owners could use in lieu of USB), an iPod AV cable (to view photo albums on a TV set), and an iPod Camera Connector (to transfer and view images directly from a digital camera to an iPod). Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection. The new fourth-generation line of iPods/Color iPods came bundled with a USB cable and an AC adapter. Malik; Hien, Tran Tinh; and Farrar, Jeremy. New Mac computers are bundled with iPhoto, while Windows users must either use the limited features within iTunes for Windows or purchase either of the Adobe products (a limited version of Adobe Album is available for download for free).

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. To manage the photo library on iPod, Mac users use Apple's iPhoto software, while Windows users can use Adobe Photoshop Album or Elements, or use a limited set of features within the free iTunes for Windows software. (Accessed on November 2, 2005, at http://www.nature.com/nature/journal/v438/n7064/full/438006a.html). Along with the new lineup, Apple also updated iTunes to version 4.9, which added podcasting capabilities to iTunes and to iPod. Nature 2005;438(7064):6. Apple Computer — as well as prominent fan sites (such as iLounge) — continued to refer to this lineup as fourth-generation iPods. Wartime tactic doubles power of scarce bird-flu drug [News article]. The price of the 60GB iPod photo, now known as iPod 60GB, dropped from $449 to $399, and Apple discontinued the $349 30GB iPod photo model.

Butler, D. On June 28, 2005, Apple Computer merged the iPod and iPod photo lines, [10] removing all monochrome models from the main iPod line, giving the 20GB iPod all of the capabilities of the former iPod photo line for $299, the same price as the previous monochrome version. The New York Times (Accessed on November 5, 2005 at http://www.nytimes.com/2005/11/05/business/05tamiflu.html). However, unlike the first iPod photos, the lower-priced 60GB and the new 30GB models lacked the dock, FireWire cable, carrying case, or AV cables (accessories valued at approximately $120). Is Bird Flu Drug Really So Vexing? Debating the Difficulty of Tamiflu [News article]. On February 23, 2005, Apple discontinued the 40GB model; which included a FireWire & USB cable and a dock, introduced a lower-priced 30GB model; which included only a USB cable and no dock, and dropped the price of the 60GB model. Pollack, Andrew. It originally came in 40GB and 60GB versions, which cost $499 and $599, respectively.

Fortune (Accessed on Nov 28, 2005 at http://money.cnn.com/2005/10/31/news/newsmakers/fortune_rumsfeld/?cnn=yes). One millimeter thicker than the standard monochrome fourth-generation iPod, iPod photo could also play music for up to 15 hours per battery charge. Rumsfeld's growing stake in Tamiflu: Defense Secretary, ex-chairman of flu treatment rights holder, sees portfolio value growing. Released on October 28, 2004, iPod photo (originally named iPod Photo — with a capital P for "Photo" — but renamed less than a month after its launch) featured a 220 x 176-pixel (maximum pixel count of 38,720), 16-bit color screen capable of displaying 65,536 colors, and the ability to store and display JPEG, BMP, GIF, TIFF, and PNG images. Oct 31, 2005. The monochrome fourth generation iPod, slightly thinner (about 1 mm less) than the third generation iPod, introduced the ability to charge the battery over a USB connection. Schwartz, Nelson . It came in one of two sizes: 20 GB for $299 and 40 GB for $399 (Apple discontinued the 40 GB model in February 2005 and began solely selling a monochrome 20 GB version).

Metabolic: Aggravation of diabetes. Originally, the fourth generation iPod had a monochrome screen and no photo capabilities, like its predecessors. Neurologic: Seizure, confusion. After many requests from users asking for these improvements to operate on earlier iPods as well, Apple on February 23, 2005, released a firmware update which brings the new menu items to first through third generation iPods. Cardiac: Arrhythmia. Other minor changes included the addition of a "Shuffle Songs" option on the top-level menu to make it more convenient for users. Digestive: Hepatitis, liver function tests abnormal. Apple also claimed that updated software in the new iPod allows it to use the battery more efficiently and increase battery life to 12 hours.

General: Rash, swelling of face or tongue, toxic epidermal necrolysis. Some users criticized the click wheel because it does not have the backlight that the third generation iPod's buttons had, but others noted that having the buttons on the compass points largely removed any need for backlighting. Safety and efficacy for prophylaxis has not been established for patients under 13 years old. In the most obvious difference from its predecessors, the fourth generation iPod carries over the click-wheel design introduced on the iPod mini. 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. In a new publicity route, Steve Jobs announced it by becoming the subject of a Newsweek magazine cover. Tamiflu is indicated for prophylaxis of influenza either during a community outbreak or following close contact with an infected individual. In July 2004, Apple released the fourth generation iPod.

Dosage for children is by weight. Although past models proved widely popular, after the release of the third generation model Apple's iPod sales skyrocketed, with a combination of effective advertising and celebrity endorsement making iPods a fashionable item. For influenza treatment, the standard dosage for patients 13 years and older is 75 mg twice daily for five days. When purchased through the online Apple Store, the iPod featured custom engraving: a purchaser could have two lines of text laser engraved on the back for free. Tamiflu is indicated for the treatment of influenza in patients 1 year and older who have had symptoms for no more than two days. The third generation iPod could not charge through USB 2.0 however). These iPods also introduced Hi-Speed USB connectivity (with a separately sold USB adapter cable.

Instead, all iPods now shipped with their hard drives formatted for Macintosh use; the included CD-ROM featured a Windows utility which could reformat them for use with a Windows PC. With the third generation iPod, Apple stopped shipping separate Mac and Windows versions of the unit. The touch-sensitive buttons, which build upon the touch-sensitive scroll wheel introduced in the second generation iPod, make the third generation iPod unique in that it has no external moving parts (other than the hold slider on the top of the unit) and is the first iPod that doesn't have its buttons surrounding the wheel. The new buttons featured red backlighting (controlled by the same preference as the screen backlight), allowing easier use in darkness.

The third generation iPod featured touch-sensitive buttons located below the display. The iPod Dock came bundled with all but the least expensive iPod, and also retails separately. This allows them to fit more easily into the new iPod Dock which Apple introduced at the same time. These iPods use a 30-pin connector called the Dock Connector — longer and flatter than a FireWire plug.

Over the life of the third generation iPod series, Apple produced 10 GB, 15 GB, 20 GB, 30 GB, and 40 GB sizes. Slightly smaller than their predecessors, they had more distinctively beveled edges. On April 28, 2003, Apple CEO Steve Jobs introduced an "ultrathin" iPod series. The second generation iPod came with carrying cases and wired remotes and it was the first generation that was compatible with Windows.

Due to the new Toshiba hard drives, the 20 GB iPod slightly exceeded its first generation counterpart in thickness and weight, while the 10 GB model was slimmer. Introduced on July 17, 2002, at Macworld in 10 GB and 20 GB capacities, the second generation iPod replaced the mechanical scroll wheel of the original with a touch-sensitive, nonmechanical one (manufactured by Synaptics), termed a "touch wheel". Perhaps somewhat an antique, the original iPod is very rare to find nowadays, as technology has, indeed, progressed to new possibilities. Although superseded by nonmechanical "touch" and "click" wheels, the circular controller design has become a prominent iPod motif.

The first generation iPod featured four buttons (Menu, Play/Pause, Back, and Forward) arranged around the circumference of the scroll wheel. Apple designed a mechanical scroll wheel and outsourced the implementation and development to Synaptics, a firm that also developed the trackpad used by many laptops, including Apple's PowerBooks. Apple announced a 10 GB version ($499) in March 2002. [9] Critics panned the unit's price, but iPod proved an instant hit in the marketplace, quickly overtaking earlier hard drive MP3 players such as the NOMAD Jukebox.

First announced on October 23, 2001, the original iPod cost $399 with a 5 GB hard drive. One can scale this proportion up; the current 30-gigabyte iPod can hold roughly 7,500 songs, though the Apple website states that 'actual formatted capacity may be lower.'. Encoding songs at higher bitrates will take up more space on the hard drive. For the first and second generation iPod, 1 gigabyte will hold 200 songs.

Note that Apple claims that 1 gigabyte of storage will hold 250, 4-minute songs in 128 kbit/s AAC. Currently, Apple sells two sizes of iPod: a 30 GB hard drive for $299, and a 60 GB model for $399. During the third generation, three sizes of iPods have coexisted in the marketplace at any given time, priced at US $299, $399, and $499. Within any generation of iPods, various models with different sizes of hard drives have come onto the market at different price points.

Five distinct generations of iPods exist, commonly known as: first, second, third, fourth and fifth generations. While all iPods have roughly the same size and the same capabilities, the design has undergone several revisions since its introduction to the market. Some of this is also taken up by the iPod's firmware. For example, a 4 GB iPod mini actually had 3.77 GiB of usable storage.

This comes about because the capacity advertised uses metric prefixes, not binary prefixes. As with most hard drive-based devices, the actual drive space available for music, photo, video and data storage does not quite attain the advertised capacity. Several product revisions have taken place since the original model of iPod appeared, leading to the existence of five distinct generations. The Harry Potter 20 GB Collector's fourth-generation iPod was replaced by the Harry Potter 30 GB Collector's iPod, which is simply a fifth-generation iPod with a Harry Potter engraving and the Harry Potter audiobooks pre-loaded.

The iPod U2 Special Edition was also discontinued. The iPod mini (4 GB and 6 GB and in various colors) are now discontinued, having been replaced by the iPod nano. The model range as of October 12, 2005 includes:. Some models come with different capacities (a higher capacity allows the storage of more music) or with different designs.

Apple currently markets three distinct players bearing the iPod name. An iPod unable to start (due to either a firmware or a hardware problem) displays the "sad iPod" image, reminiscent of the sad Mac icon of earlier Macintosh computers. iPods with FireWire ports can be put into FireWire Disk Mode, in which it behaves like a FireWire hard drive without any of the additional iPod functionality. Fourth and fifth generation iPods, second generation iPod minis, iPod nanos and iPod shuffles automatically pause playback when headphones are unplugged from the headphone jack, and turn on when you put the headphones into the headphone jack.

Setting this switch to display orange will make the buttons and scroll wheel unresponsive, so that users do not activate them accidentally. A 'Hold' switch also exists on the top of the unit. (Note that fourth and fifth-generation iPods, iPod minis, and iPod nanos incorporate these buttons into the "click wheel" scroll wheel.). iPods (other than the iPod shuffle) have five buttons:.

iPod contains a small internal speaker which generates the scroll-wheel clicks and alarm clock beep sound, but this internal speaker cannot play music. A servicer can pry the iPod open by carefully inserting a small non-metal screwdriver to pull the metal away from the clips. The plastic front of the case has clips which lock under a ridge inside the rim of the metal case back. The unit's case snaps together, with no screws or glue involved (though the fourth generation has some glue holding the battery in place).

From left to right:. This photograph shows the internal view of a third-generation iPod:. The iPod mini uses the "Espy Sans" font (previously seen in eWorld, the Newton, and Copland), while the color fourth-generation iPods (previously known as iPod photo) and fifth-generation iPods use Myriad, Apple's current corporate typeface. Until the release of iPod mini, the user interface of all iPods used "Chicago", the font used on the original Macintosh computer from 1984.

More recent iPods, such as the nano and 5th Generation, also incorporate the "brushed-metal" effect, previously used in iTunes before version 5.0, in their stopwatch and screen lock features. (The founder of Pixo had worked on the Apple Newton, a personal digital assistant formerly produced by Apple.) The Pixo libraries provide the user interface, though the iPod photo has incorporated some visual elements from Mac OS X, such as the animated Aqua style progress bar. His team integrated the core firmware from PortalPlayer with the user interface library developed by Pixo. Jeff Robbin headed the iPod firmware team at Apple.

Apple has not yet released a Linux version of the software used to flash the firmware of the iPod. As of 2005 only gtkpod offers such functionality for Linux and other Unix variants; however in early 2006, AmaroK will have full support for most iPods. However, a special database file serves to list the songs available to play, so a program such as iTunes is required to upload songs. The iPod will also charge from any powered USB or Firewire port, regardless of software support.

The iPod uses standard USB and FireWire mass-storage connectivity, and therefore any system with mass-storage support can mount it and use it as an external hard drive. Running this interface on an iPod photo has been known to cause irreparable problems. The linux interface is known as "Podzilla". [8].

A SourceForge project exists for the project [7], and copious documentation appears online. It currently supports first through third generation iPods, and features simple installers for Mac OS X and Windows. The iPodLinux project has successfully ported an ARM version of the Linux kernel to run on iPods. The ability to use an iPod as a boot disk for a Macintosh computer was lost when Apple removed FireWire with the introduction of the fifth-generation iPod since none of the G5-based Macintosh models can boot from an external USB drive.

HFS+ leaves slightly more space available to store data, and it allowed the iPod to serve as a boot disk for a Macintosh computer. Currently, iPods ship with FAT32 by default and are reformatted for use with Macintosh computers, but they previously shipped formatted for Mac and would be reformatted for PC. An iPod with its hard drive formatted as HFS+ operated only with a Macintosh, because Windows does not support HFS+, but since the Macintosh could handle FAT32, an iPod formatted as FAT32 could operate with a Macintosh as well as with a PC. [5] Apple released a Windows version of iTunes on October 16, 2003 [6]; previously, Windows users needed third-party software such as Musicmatch Jukebox (included with Windows iPods before the release of the Windows version of iTunes), ephPod, or XPlay to manage the music on their iPods.

The original iPod interacted only with Macintosh computers running Mac OS 9 or Mac OS X until July 17, 2002, when Apple began selling a Windows-compatible iPod, with its internal hard drive formatted in FAT32 instead of the original HFS Plus. [4]. The signature earphones have such good recognition characteristics that they can become a liability – after a 24% rise in robbery and a 10% increase in grand larceny in the NYC subway system, a spokesperson for the New York City Police Department suggested that iPods might be behind the increases. This is often easily solved by applying a small amount of suction to the problem earphone.

They are also known to develop a clicking noise at volume peaks, due to the membrane being displaced. Users rate the substandard bass response as the most apparent negative characteristic found in the standard headphones. Like most headphones that come bundled with other hardware, the stock white earbuds are fairly low quality, and some users choose to replace them. Despite the fact that new generations of the iPod now appear in black as well as white, the cords still remain white.

The white cords have become symbolic of the iPod brand, and advertisements for the devices feature them prominently. All iPods come with earbud headphones with distinctive white cords, a color chosen to match the design of the original iPod. (The 60GB fifth-generation iPod holds 64 MiB of RAM, to further extend battery life.). For example, an iPod could spin the hard disk up once and copy about 30 MiB of upcoming songs on a playlist into RAM, thus saving power by not having the drive spin up for each song.

All iPods, except for the 60GB fifth-generation iPod, have 32 MiB of RAM, a portion of which holds the iPod OS loaded from the firmware and the vast majority of which serves to cache songs loaded from the hard drive. The iPod has a 32-MiB flash ROM chip which contains a bootloader, a program that tells the device to load the operating system from another medium (in this case, the hard drive). The iPod mini uses one-inch hard drives made by Hitachi. iPods use 1.8-in (46-mm) ATA hard drives (with a proprietary connector) made by Toshiba.

The first three generations of iPod used two ARM 7TDMI-derived CPUs running at 90 MHz, while later models have variable speed chips which run at a peak of 80 MHz to save battery life. The iPod shuffle has a built-in USB connector that plugs into a standard USB port for recharging and for data transfer, but a connector for AC charging can be purchased. Newer iPods, iPod minis and iPod nanos use a proprietary 30-pin dock connector to connect the iPod to a computer’s FireWire or USB port with a proprietary cable. First- and second-generation iPods had a standard FireWire connection port.

Both USB-based and FireWire-based power adapters exist. iPods can recharge their internal batteries using either FireWire (all generations) or USB power (only fourth generation and later) while connected to a computer or to an iPod AC power adapter. Apple stopped shipping FireWire cables with iPods in favor of only using Hi-Speed USB (USB 2.0), more than likely a cost-cutting and size-saving measure since many Windows-based PCs do not have FireWire ports. Except for iPod shuffle, iPod nano, and fifth-generation iPod, all previous models of iPod offered FireWire connectivity.

The game, "Rock and Pop Trivia Quiz" from Coolgorilla takes the listener through 40 narrated questions on well known Rock & Pop artists. December 2005 saw the release of one the first iPod Game to make use of the iPod's ability to act as a "Sonic Gaming Platform". All iPods (except the shuffle) feature "Brick", a clone of the Breakout arcade game from Atari (originally created by Apple cofounder Steve Wozniak) along with three other games:. iPods (with the exception of the iPod shuffle) also feature games.

However, iPod has limitations as a PDA, since users cannot edit this information on the iPod but only on a computer. It can also display notes, and hence host simple games and store restaurant information. [3]. Repeated calls to Apple from consumers have yielded no commitment to correct this problem as of January, 2006.

No workaround (including mentally converting times when reading them) is functionally acceptable due to the combined behaviours of iSync, iCal and the iPod with regards to converting events between timezones. Their timezones are excluded from the iPod's firmware, leaving them unable to properly sync calendar events and alarms to their devices. The limited PDA calendar functions of the iPod are somewhat tainted for users from Newfoundland and parts of Australia. However the files can be manually dragged and dropped into the correct directory on the iPod.

Although Mozilla Calendar and Mozilla SunbirdiCalendar file format used by iCal and the iPod, there is no way to automatically sync schedules across from these programs. With the 2005 release of iTunes 5.0, Apple integrated contact/schedule syncing into iTunes and added the ability for Windows users to synchronize their contacts and schedules from Microsoft Outlook and Outlook Express. Since January 2003, Mac users have been able to synchronize their contacts and schedules Address Book and iCal to their iPods through iSync. In addition to playing music and storing files, the iPod has limited PDA functionality.

iTunes lacks the ability to transfer songs from iPod to computer because of legality issues. Apart from iTunes there are also several third-party applications available that can be used to transfer songs to the iPod. Users may also set a rating (out of 5 stars) on any song, and can synchronize that information to an iTunes music library. iTunes can automatically synchronize a user's iPod with specific playlists or with the entire contents of a music library each time an iPod connects to a host computer.

Apple designed the iPod to work with the iTunes media library software, which lets users manage the music libraries on their computers and on their iPods. Midis can also be played on iPods, but they first must be converted to the MP3 format by choosing the "advanced" menu on iTunes. Reviewers have criticized the iPod's inability to play some other formats, in particular the Ogg Vorbis and FLAC formats. WMA files with copy protection cannot be played in iTunes or be copied to an iPod.

The Windows version of iTunes can transcode non copy-protected WMA files to an iPod supported format. The fifth-generation iPod can also play .m4v (H.264) and .mp4 (MPEG-4) video file formats. iPods can play MP3, WAV, AAC/M4A, Protected AAC, AIFF, Audible audiobook and Apple Lossless audio file formats. 6,928,433: "Automatic hierarchical categorization of music by metadata", which Creative dubbed the "Zen Patent", granted on 9 August 2005).[2].

Patent No. Also in August 2005, Creative Technology, one of Apple's main rivals in the MP3 player market, announced that it too held a patent on part of the music selection interface used by the iPod (U.S. Apple's application to the United States Patent and Trademark Office for a patent on "rotational user inputs", as used in the iPod's interface, received a third "non-final rejection" (NFR) in August 2005. In 2005, Apple Computer faced two lawsuits claiming patent infringement by the iPod and its associated technologies: Advanced Audio Devices claimed the iPod breached their patent on a "music jukebox" (See Hong Kong-based IP portfolio company Pat-rights filed suit on behalf of inventor Keung Tse Ho,) claiming that Apple's FairPlay technology breached their patent on "protection of software against unauthorized use".[1].

Apple has posited that the iPod has a "halo effect", encouraging users of non-Apple products to switch to other Apple products, such as to Macintosh computers. The iPod has sold at a tremendous rate, now past 42 million units since its release. As of October 2004, iPod dominated digital music player sales in the United States, with over 90% of the market for hard-drive-based players and over 70% of the market for all types of players. In 2003, Apple released third-generation iPods that included a single CD that included a Windows version of the iTunes software along with the Mac version.

The actual iPods could work with either system (though to work with Windows, they had to use the FAT32 filesystem, Mac iPods could use either the FAT32 or HFS Plus filesystem). The only difference though was the bundled software, since there was no iTunes for Windows at the time, the Windows iPods came packaged with Musicmatch software. In 2002, Apple released the second-generation iPod in two versions, one for Mac users and one for Windows users. Apple’s Hardware engineering chief Jon Rubinstein assembled a team of engineers to design and build the first iPod in less than a year, and it was unveiled by CEO Steve Jobs on October 23, 2001 as a Mac-compatible product with a 5GB hard drive that put “1,000 songs in your pocket.”.

While digital cameras, camcorders and organizers had well-established markets, the company found digital music players lacking in quality and Apple decided to develop its own. Development of the iPod grew out of Apple’s digital hub strategy, as the company was creating software applications for the growing number of digital devices being snapped up by consumers. Recently, some media have started referring to the generation primarily born in the late 1980s, and which in particular has made the iPod popular, as the iGeneration, suggesting that the "i" family of products may have a far-reaching cultural impact. When Apple first introduced the iMac, the "i" stood for internet (as well as a possible tongue-in-cheek reference to Steve Jobs's title with the company at the time, interim CEO, abbreviated iCEO), meaning that the iMac shipped with everything needed for a connection, but the prefix stuck, as the brand recognition associated with it has positive effects on the sales of Apple products.

The company has many other products with a lowercase "i" in front of the name, including iSight, iChat, iTunes, iDVD, iBook, and much more. Apple's web site reflects this usage (for example, "iPod incorporates the same touch-sensitive Apple Click Wheel that debuted on iPod mini"), which resembles Apple's use of the words Macintosh or iMac. Apple Computer often refers to the player as iPod, without use of the definite article the. .

The most recent incarnations of iPod and iTunes have video playing and organization features. iTunes is a music jukebox application that stores a comprehensive library of the user's music on his/her computer, as well as being able to play and rip music from a CD. The bundled software used for uploading music, photos, and videos to the iPod is called iTunes. The iPod is currently the world's best-selling digital audio player.

As of January 2006, the lineup consists of the fifth-generation iPod which can play videos, the iPod nano which has a color screen, and the iPod shuffle; all three iterations were released in 2005. Discontinued versions of the iPod include two generations of the popular iPod mini and four generations of the full-sized iPod, all of which had monochrome screens except for the fourth-generation iPod with color screen (previously sold as iPod photo before it replaced the monochrome iPod in the top line). Like most digital audio players, an iPod can serve as an external data storage device when connected to a computer. The standard iPod model stores media on a built-in hard drive, while the smaller iPod shuffle and iPod nano use flash memory.

Devices in the iPod family provide a simple user interface designed around a central scroll wheel (with the exception of the iPod shuffle). iPod is a brand of portable digital media player designed and marketed by Apple Computer. Accessed on October 13, 2005. Notes." MP3 Newswire.

"Apple Portable Does Video. ^  Richard Menta. Accessed on August 22, 2005. "Eminem settles with Apple over iPod commercial." c|net News.com.

^  Ina Fried. Accessed on August 22, 2005. "New iPod ads feature U2." Macworld. ^  Jim Dalrymple.

Accessed on August 22, 2005. "Pepsi ads wink at music downloading." USA Today. ^  Theresa Howard. The first iPod television ad.

^  Beat. Accessed on August 23, 2005. ^  "Hewlett-Packard to Stop Reselling iPods." Forbes. Accessed on January 18, 2006.

^  "Apple Reports First Quarter Results." Apple. Accessed on August 23, 2005. ^  "Apple Reports Third Quarter Results." Apple. Accessed on August 22, 2005.

"It's iPod's Revolution: We Just Live in It." Fortune. ^  Andy Serwer. Stan Ng — Director of iPod Product Marketing. Danika Cleary — iPod Product Manager.

Sanjeev Kumar. Jeff Robbin. Tony Fadell — Apple Vice President of iPod Engineering. Jonathan Ive — Apple Vice President of Industrial Design.

[57]. Apple announced on October 14, 2005 that Jon Rubinstein will retire on March 31, 2006 and be succeeded by Tony Fadell. Jon Rubinstein — Apple Senior Vice President of the iPod Division. Steve Jobs — CEO of Apple.

It featured Wynton Marsalis performing "Sparks". The ad is in blue and features many circular shapes in the background. On January 10, 2006, Apple premiered a new silhouette ad, based on the modified silhouette campaign (read above). [56].

The silhouette of Eminem also shows more highlights and shadows. Instead of a solid background, the background is a busy montage of different shapes and buildings in similar tones of orange. The other was a video of Eminem performing Lose Yourself in a modified version of the silhouette style. One featured a video of U2's Original of the Species playing on the new iPod's screen, held by a hand in the same style as the iPod nano adverts.

On October 12, 2005 Apple introduced two ads for the iPod fifth generation. They focused instead on the diminutive size of the product, with live-action shots of a hand holding an iPod nano on a black background, flipping it round and fiddling with it, to show how small and light it was. The TV adverts that accompanied the release of the iPod nano were the first for a long time not to incorporate the silhouette theme. The giveaway lasted for two months and included 100 million codes under the caps of Pepsi drinks, of which only 5 million were redeemed by its end.

In conjunction, Pepsi also launched ads featuring young teenagers who had been accused of unauthorized filesharing by the RIAA, who go on to say they will still download music for free thanks to the Pepsi iTunes Giveaway. Each bottle had a 1:3 chance of winning a free download. On February 1, 2004, during the Super Bowl, Pepsi and Apple kicked off their promotional deal to include a free iTunes download under the caps of Pepsi bottled soda. The iPod shuffle was released alongside TV commercials featuring silhouettes dancing on a green background with Apple's shuffle symbol moving underneath them, showing their intent on incorporating their silhouette campaign with each of their products.

[55]. To commemorate the launch of the U2 iPod, Apple released an ad featuring the music video of Vertigo (changed to characteristic iPod silhouettes). These commercials featured popular songs, such as The Vines' Ride, The Caesars' Jerk it Out, Gorillaz' Feel Good Inc., Steriogram's Walkie-Talkie Man, Jet's Are You Gonna Be My Girl, Propellerheads' Take California, Ozomatli's Saturday Night, N.E.R.D.'s Rock Star (Jason Nevin's Mix), Franz Ferdinand's Take Me Out, Daft Punk's Technologic, and many more. It featured silhouettes dancing to music while listening to iPods.

In October 2003, Apple released their first TV commercial of the silhouette campaign, which had already been featured for some time in print. The commercials featured a wide range of music, including The Who's My Generation, Sir Mix-a-lot's Baby Got Back, Pink's There You Go, and Eminem's Lose Yourself. The ads featured informally dressed persons wearing iPods and giving animated silent renditions of popular songs, accompanied by dancing, air guitar, and other performances. In April 2003, Apple introduced a new ad campaign in conjunction with the launch of the iTunes Music Store.

[54]. The ad can be viewed on Apple's web site. The first iPod ad, featuring the tagline "A thousand songs, in your pocket" was launched alongside iPod in November 2001. [31] [32].

Honda will be the first to include text-to-speech capabilities that allow drivers to search for playlists, artist and album names or genre. More than thirty percent of the cars in the United States now include iPod support. With these deals Apple now has 15 car companies worldwide planning to offer iPod integration. Apple announced in September 2005 that they now have deals with Acura, Audi, Honda and Volkswagen to integrate iPod into their car stereos during the year.

[28] [29] [30]. Apple announced at Macworld Expo in January 2005 that Mercedes-Benz USA, Volvo, Nissan, Alfa Romeo and Ferrari would offer similar systems. The iPod attached to a cable harness in the car's glove compartment and allowed the driver to create up to five unique "BMW playlists" that were displayed through the vehicle's radio head unit. [27] The interface allowed drivers of late-model BMW vehicles to control their iPod through the built-in steering wheel controls and the radio head unit buttons.

BMW released the first iPod automobile interface to come from an automotive company. Volkswagen: 2006 Beetle. Volvo: S40, S60, S80, V50, V70, XC70, XC90. Scion: xA, xB, tC.

Mini: Cooper, Cooper S. Mercedes-Benz: C-Class, CLK, CLS, E-Class, SLK, M-Class, R-Class. BMW: Z4, X3, X5. Acura RL, TL using Acura Music Link (option only - installation and parts required).

iPod shuffle (512 MB and 1 GB). iPod nano (2 GB and 4 GB). iPod (30 GB and 60 GB). 'Center' (the button in the center of the scroll wheel; this selects a menu or a menu item).

'Next' (which skips forward through tracks in play). 'Previous' (which skips back through tracks in play). 'Play/Pause' (which plays or pauses the track in play). 'Menu' (which backs up one level in the menus).

A hole on the bottom of the case allows access to the dock connector port on the circuit board. Wires connect the ports and switch on the top of the case to a small plug. The rear of the iPod. The layer of rubber also helps to protect a spinning hard drive from shock damage while the owner of the iPod moves about.

The hard drive, surrounded by a layer of soft rubber which also extends beneath it to insulate it from the circuit board. The lithium ion battery. Note three connectors: the battery connects in the lower-right corner; the hard drive connector lies to the left of the black area in the lower left; and the headphone jack, wired remote control jack, and Hold switch (all located on the top of the iPod) connect as a single plug in the top right. The lighter green circuit board controls the iPod (and leaves room for the battery to fit beside it), and the darker green board beneath it controls the touch-scroll wheel and the buttons.

The front of the iPod casing (facedown). An intact third-generation iPod. This allows the user to read small text files. Notes: iPod also has the function to read EBooks through use of the Notes Function.

No record is kept of the score, and there is no limit on the amount of songs played; however, the songs repeat after the first 100. Music Quiz became available through a free firmware update for third generation iPods released in October 2003 and later came standard with the iPod mini and fourth generation iPods. The faster the users choose the right song, the more points they get. A song drops off the list every few seconds.

The game plays a portion of a random song and prompts the user to identify it from a list of 5 (or of 4 on the iPod mini). Music Quiz: an interactive music quiz featuring the user's own songs. Solitaire: a simple card game resembling the Klondike solitaire card game. Parachute is similar to the Apple II game Sabotage by Mark Allen.

Parachute: a game in which the user controls a turret and attempts to shoot down paratroopers and the helicopters which release them.

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