|Systematic (IUPAC) name|
|Licence data||US Daily Med:|
|Pregnancy cat.||B1 (AU) C (US)|
|Legal status||Prescription Only (S4) (AU) POM (UK) ℞-only (US)|
|Metabolism||Hepatic, to GS4071|
|Mol. mass||312.4 g/mol|
|(what is this?)|
Oseltamivir INN //, marketed under the trade name Tamiflu, is an antiviral licensed to prevent or slow the spread of influenza A and influenza B (flu) virus between cells in the body by stopping the virus from chemically cutting ties with its host cell. The drug is taken orally in capsules or as a suspension. Oseltamivir is a prodrug, a (relatively) inactive chemical, which is converted into its active form by metabolic process after it is taken into the body. It was the first orally active neuraminidase inhibitor commercially developed. It was developed by C.U. Kim, W. Lew, and X. Chen of US-based Gilead Sciences, and is marketed by Genentech.
Oseltamivir's benefits in those who are otherwise healthy do not appear to outweigh its risks. No benefit has been found in those with other health problems. Prior to 2013, oseltamivir's effectiveness was debated as its manufacturer, Roche, originally refused to release the data from all of its trials for independent analysis (all data was not available to the official bodies that decided to licence/approve it). Together, these published studies suggest that oseltamivir reduces the duration of symptoms by 0.5–1 day. It is unclear whether this medication affects transmission of influenza in adults. It does not appear to change the rate of complications from influenza, such as the risk of hospitalization or pneumonia. However, it can increase rates of vomiting.
As of December 15, 2010[update], the World Health Organization (WHO) reported 314 samples of the prevalent 2009 pandemic H1N1 flu tested worldwide have shown resistance to oseltamivir. However, the predominant strains of both influenza A and influenza B active during the 2012-2013 flu season in the US are sensitive to oseltamivir.
- 1 Medical use
- 2 Adverse effects
- 3 Resistance
- 4 Mechanism of action
- 5 Commercial issues
- 6 Personal stockpiling
- 7 Veterinary use
- 8 Chemical synthesis
- 9 Manufacturing
- 10 See also
- 11 References
- 12 Further reading
- 13 External links
When used for treatment or prevention in those that are otherwise healthy, it does not appear to have benefits that outweigh the risks.
The standard recommended dose incompletely suppresses viral replication in at least some patients with H5N1 avian influenza, increasing the risk of viral resistance and rendering therapy less effective. Accordingly, higher doses and longer durations of therapy have been suggested for treatment of patients with the H5N1 virus.
There is low to moderate evidence that it decreases the risk of getting influenza by 1% to 12% in those exposed. It is unclear whether it affects the risk of needing to be hospitalized or the risk of death. Oseltamivir is indicated for the treatment and prevention of infections due to influenza A and B viruses. The predominant strains of both influenza A and influenza B active during the 2012-2013 flu season in the US are sensitive to oseltamivir.
A 2012 Cochrane review maintains that significant parts of the clinical trials still remains unavailable for public scrutiny, and that the available evidence is not sufficient to conclude that oseltamivir decreases hospitalizations from influenza-like illnesses. As of October 2012, 60% of Roche's clinical data concerning oseltamivir remains unpublished.
Roche commissioned an independent reanalysis of its data in 2011. One of the authors had received income from an organization sponsored by Roche previously but they were not funded by Roche for this analysis. They concluded that early oseltamivir use reduced the number of lower respiratory tract infection treated with antibiotics from 9.3% to 5.9% in hitherto healthy adults and children. No benefit occurred in those without an infection with influenza.
Common adverse drug reactions (ADRs) associated with oseltamivir therapy (occurring in over 1 percent of clinical trial participants) include: nausea, vomiting, diarrhea, abdominal pain, and headache. Rare ADRs include: hepatitis and elevated liver enzymes, rash, allergic reactions including anaphylaxis, and Stevens–Johnson syndrome.
Various other ADRs have been reported in postmarketing surveillance, including: toxic epidermal necrolysis, cardiac arrhythmia, seizure, confusion, aggravation of diabetes, and haemorrhagic colitis.
There are concerns that oseltamivir may cause dangerous psychological, neuropsychiatric side-effects including self-harm in some users. These dangerous side-effects occur more commonly in children than in adults. This stems from cases in Japan, where the drug is most heavily prescribed, consuming 60 percent of the world's production.
In March 2007, Japan's Health Ministry warned that oseltamivir should not be given to those aged 10 to 19. The Ministry had previously decided, in May 2004, to change the literature accompanying oseltamivir to include neurological and psychological disorders as possible adverse effects, including impaired consciousness, abnormal behavior, and hallucinations.
According to Japan's Health Ministry, between 2004 and March 2007, fifteen people aged 10 to 19 have been injured or killed by jumps or falls from buildings after taking oseltamivir, and one 17-year-old died after he jumped in front of a truck. A renewed investigation of the Japanese data was completed in April 2007. It found that 128 patients had been reported to behave abnormally after taking oseltamivir since 2001. Forty-three of them were under 10 years old, 57 patients were aged 10 to 19, and 28 patients were aged 20 or over. Eight people, including five teens and three adults, had died from these actions.
In October 2006, Shumpei Yokota, a professor of pediatrics at Yokohama City University, released the results of research involving around 2,800 children, which found no difference in the behavior between those that took oseltamivir and those that did not. Chugai Pharmaceutical Co. (which produces oseltamivir in Japan) gave Yokota's department 10 million yen (about US$105,000) over five years.
To determine whether to lift the 2007 ban, a research team from the Japanese Health, Labour and Welfare Ministry studied 10,000 children under the age of 18 who had been diagnosed with influenza since 2006. The study was finalized in April 2009. Taking into account all degrees of abnormal behavior, including minor behavioral problems such as incoherent speech, the study found children that took oseltamivir were 54 percent more likely to exhibit abnormal behaviour than those that did not take the drug. When the team limited its analysis to children that had displayed serious abnormal behavior that led to injury or death, it found those that had taken oseltamivir were 25 percent more likely to behave unusually.
In November 2006, the U.S. Food and Drug Administration (FDA) amended the warning label to include the possible side-effects of delirium, hallucinations, or other related behavior. This went further than the FDA's previous pronouncement, from a year before, that there was insufficient evidence to claim a causal link between oseltamivir use and the deaths of 12 Japanese children (only two were from neurological problems, although more have died since then). The change to a more cautionary stance was attributed to 103 new reports the FDA received of delirium, hallucinations, and other unusual psychiatric behavior, mostly involving Japanese patients, received between August 29, 2005 and July 6, 2006. This was an increase from the 126 similar cases logged between the drug's approval in 1999 and August 2005.
In April 2007, South Korea issued a safety warning against prescribing oseltamivir to teenagers except in special cases.
A joint investigation by the British Medical Journal (BMJ) and British TV Channel 4 published in the BMJ on December 8, 2009, concluded that in otherwise-healthy adults they "have no confidence in claims that oseltamivir reduces the risk of complications and hospital admission in people with influenza" and believe it should not be used in routine control of seasonal influenza. There was also concern about underreporting of side-effects of the drug. In contrast, according to the BMJ, Roche has stated in media briefings that oseltamivir reduced hospital admissions by 61 percent; secondary complications (including bronchitis, pneumonia, and sinusitis) by 67 percent in otherwise-healthy individuals and lower respiratory tract infections requiring antibiotics by 55 percent.
BMJ editor Dr. Fiona Godlee said "claims that oseltamivir reduces complications have been a key justification for promoting the drug's widespread use. Governments around the world have spent billions of pounds on a drug that the scientific community has found itself unable to judge."
2009 pandemic H1N1 flu
A study published in the June 2009 issue of Nature Biotechnology also emphasized the need for augmentation of oseltamivir stockpiles with additional antiviral drugs, including zanamivir (Relenza), based on an evaluation of the performance of these drugs in the scenario that the 2009 H1N1 neuraminidase (NA) were to acquire the oseltamivir-resistance mutation.
Resistance to Oseltamivir was widespread in seasonal flu from 2007-2009. In the 2007-2008 flu season, the US CDC found 10.9% of H1N1 samples (n=1,020) to be resistant. In the 2008-2009 season, the proportion of resistant H1N1 increased to 99.4%. Other seasonal strains (H3N2, B) showed no resistance. All Oseltamivir-resistant strains maintained sensitivity to zanamivir.
Resistance to Oseltamivir has been low in seasonal flu from 2009-2012. In the 2010-2011 flu season, the US CDC reported maintained Oseltamivir sensitivity in 99.1% of H1N1 (n=4,229), 99.8% of H3N2 (n=806), and 100% of Influenza B (n=723) samples tested. As of January 2012, the US and European CDCs were reporting sensitivity to Oseltamivir for all (n=103) seasonal flu samples tested since October 2011.
Mutant H3N2 influenza A virus isolates resistant to oseltamivir were found in 18 percent of a group of 50 Japanese children treated with oseltamivir in 2002-2003. 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. claim to have used more rigorous detection techniques than previous studies. Inadequate dosage may also have been an issue.
In 2007, Japanese investigators detected neuraminidase-resistant influenza B virus strains in individuals having not been treated with these drugs. The prevalence was 1.7 percent. According to the CDC, as of October 3, 2009[update] no influenza B strains tested have shown any resistance to oseltamivir.
H5N1 avian influenza
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. 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 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 oseltamivir could lead to underdosage and, thus, the emergence of resistant strains of H5N1.
Resistance is of concern in the scenario of an influenza pandemic (Wong and Yuen 2005), and may be more likely to develop in avian influenza than seasonal influenza due to the potentially longer duration of infection by novel viruses. Kiso et al. suggest "a higher prevalence of resistant viruses should be expected" during a pandemic. Resistant strains have also appeared in the EU.
Mechanism of action
Oseltamivir is a neuraminidase inhibitor, serving as a competitive inhibitor of the activity of the viral neuraminidase (NA) enzyme upon sialic acid, found on glycoproteins on the surface of normal host cells. By blocking the activity of the enzyme, oseltamivir prevents new viral particles from being released by infected cells.
The patent for oseltamivir is held by Gilead Sciences and is valid at least until 2016. Gilead licensed the exclusive rights to Roche in 1996. The drug does not enjoy patent protection in Thailand, the Philippines, Indonesia, and several other countries. Gilead is politically well connected: Donald Rumsfeld served as chairman from 1997 until he became U.S. Secretary of Defense in 2001; former Secretary of State George Shultz and the wife of former California Governor Pete Wilson serve on the board.
Oseltamivir 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, Israel, United States, and Australia – stockpiled quantities of oseltamivir in preparation for a possible pandemic.
In late October 2005, Roche announced 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. Sales were suspended in Hong Kong as well, and on November 8, 2005, also in China. Roche said it would instead send all supplies to China's health ministry.
On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir. The week before, Thai authorities said they would begin producing generic oseltamivir, claiming that Roche had not patented Tamiflu in Thailand. The first Thai generic oseltamivir was produced in February 2006, and was to have been available to the public in July 2006.
In November 2005, U.S. President George W. Bush requested that Congress fund US$1 billion for the production and stockpile of oseltamivir, after Congress had already approved $1.8 billion for military use of the drug. Defense Secretary Rumsfeld recused himself from all government decisions regarding the drug.
In May 2006, the WHO asked Roche to be ready to ship an emergency stockpile of oseltamivir to Indonesia if needed. The alert was in response to suspected human-to-human transmission within a family, and was planned to last for two weeks.
In December 2008, the Indian drug company, Cipla won its case in India's court system allowing it to manufacture a cheaper generic version of Tamiflu, called Antiflu. In May 2009, Cipla won approval from the WHO certifying that its drug Antiflu was as effective as Tamiflu, and Antiflu is included in the WHO list of prequalified medicinal products.
Production shortage/shikimic acid
In early 2005, Roche announced a production shortage. In 2006, however, Roche said production was about to reach 400-million treatment courses annually, that "capacity was well in excess of total government orders placed to date," and "the supply shortage no longer exists." Total government orders between 2005 and 2007 were estimated to be around 200 million treatment doses. In fact, Roche CEO William Burns said a shortage of orders could cause Roche to reduce production in the future. Roche attributes production increases in part to its agreements with 15 external contractors in 9 countries.
While current demand for seasonal influenza treatment and pandemic stockpiling are being met, it is unclear what the situation would be if a pandemic actually started. Doctors are now testing a doubling of the standard dose with the hope it would cut H5N1 influenza virus death rate. If this became the new standard, it would decrease the effective supply.
According to Roche, the major bottleneck in oseltamivir production is the availability of shikimic acid, which cannot be synthesised economically and is effectively isolated only from Chinese star anise, an ancient cooking spice; the herb is also used in traditional Chinese medicine. 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 was a worldwide shortage of Tamiflu in 2005. Star anise is grown in four provinces in China and harvested between March and May. It is also produced in Lạng Sơn Province, Vietnam. The shikimic acid is extracted from the seeds in a ten-stage process. Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 oseltamivir 75 mg capsules.
Some academic experts[who?] 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. Recently, biosynthetic pathways in Escherichia coli have been enhanced to allow the organism to accumulate enough shikimic acid to be used commercially. Canadian generic drug company Apotex is attempting[when?] to modify oseltamivir to use a synthetic alternative to shikimic acid. Other potential sources of shikimic acid include the sweetgum and ginkgo trees. Quinic acid, derived from the bark of the cinchona tree, is a potential alternative base material for the production of oseltamivir. In addition, aminoshikimic acid, biosynthesized via fermentation of genetically modified bacteria, is a very promising alternative starting material for the production of oseltamivir.
The multistep synthesis above shows that, although the major bottleneck for Roche may be the availability of shikimic acid, production of oseltamivir is very involved. Increasing production volume (by Roche or others) would require construction of extensive new facilities (which may not be amenable to scaleup and, even if identical on paper, may not necessarily produce acceptable yields), and, even if current facilities could handle a larger feedstock quantity, there would be a delay in production as the material makes it down the pipeline (~6 months or so). Producing large amounts of Tamiflu not only takes months to complete but is also hazardous. Some of the steps in the synthesis require careful handling and relatively mild reaction conditions, as they involve the use of potentially explosive azide chemistry. Roche has explored ways to speed up production. It has developed an azide-free allylamine route from the epoxide to Tamiflu. It has also crafted routes that do not rely on (–)-shikimic acid: A Diels-Alder-based one that uses furan and ethyl acrylate as starting materials, and another that relies on catalytic hydrogenation of an isophthalic acid derivative followed by enzymatic desymmetrization. In addition, Frost and Guo at Michigan State University have developed a microbial synthesis of aminoshikimic acid, which could reduce the need for azide chemistry if used as a starting material.
A short supply of oseltamivir prompted some individuals to stockpile the drug. Several American states issued advisories strongly discouraging this practice. Production has since caught up with current demand (see above).
In The New England Journal of Medicine, Anne 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 have only ten pills of 75 mg each (the current[when?] recommended dosage for oseltamivir), but this may be insufficient for the treatment of H5N1.
Another argument against individual stockpiling is that limited drugs should be kept for more strategic 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 having come down with avian influenza. Ethical arguments are sometimes made as to whether affluent people or nations should have preferred access to antiviral medications. Illegal importation might divert the drug from poorer countries, where the risk of avian influenza is actually higher. A counter argument is that it is difficult to justify prohibition of individual stockpiling, when some of the same arguments are pertinent to corporate stockpiling, which is both allowed and encouraged.
A third argument is that it would be difficult for home users to determine whether illegally imported Tamiflu is counterfeit. In December 2005, 53 packages of counterfeit Tamiflu tablets 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 the appearance of counterfeit Tamiflu outside of the United States: incorrectly labeled tablets found in Holland, which contained only vitamin C and lactose.
An argument in favor of individual stockpiling is that Roche is on the record as saying that, without more orders, they may have to actually curtail production. Individual stockpiling could bring market forces to play, maintaining production capacity and allowing the total supply on hand to be higher in case demand again outstrips production in the future, for instance, during a sudden influenza outbreak.
There have been reports of oseltamivir's reducing disease severity and hospitalization time in canine parvovirus infection. The drug may limit the ability of the virus to invade the crypt cells of the small intestine and decrease gastrointestinal bacterial colonization and toxin production.
Aqueous solubility of oseltamivir in form of phosphate salt is 588 mg/ml at 25 °C (77 °F).
The current[when?] production method features a number of reaction steps, two of which involving potentially hazardous azides. A reported azide-free Roche synthesis of the drug is summarized graphically below
Oseltamivir is marketed by Genentech under the trade name Tamiflu, as capsules (containing oseltamivir phosphate 98.5 mg equivalent to oseltamivir 75 mg) and as a powder for oral suspension (oseltamivir phosphate equivalent to oseltamivir 6 mg/ml).
- Burch J, Corbett M, Stock C et al. (September 2009). "Prescription of anti-influenza drugs for healthy adults: a systematic review and meta-analysis". Lancet Infect Dis 9 (9): 537–45. doi:10.1016/S1473-3099(09)70199-9. PMID 19665930.
- Lew W, Chen X, Kim CU (June 2000). "Discovery and development of GS 4104 (oseltamivir): an orally active influenza neuraminidase inhibitor". Curr. Med. Chem. 7 (6): 663–72. doi:10.2174/0929867003374886. PMID 10702632.
- "Tamiflu Approval, Review, and Labeling Information". Drugs@FDA. U.S. Food and Drug Administration (FDA). Retrieved 2012-11-08.
- Coenen, B; Van Puyenbroeck, K; Verhoeven, V; Vermeire, E; Coenen, S (2013). "The value of neuraminidase inhibitors for the prevention and treatment of seasonal influenza: a systematic review of systematic reviews". In Jefferson, Tom. PLoS ONE 8 (4): e60348. Bibcode:2013PLoSO...860348M. doi:10.1371/journal.pone.0060348. PMC 3614893. PMID 23565231.
- Ebell, MH; Call, M; Shinholser, J (April 2013). "Effectiveness of oseltamivir in adults: a meta-analysis of published and unpublished clinical trials". Family practice 30 (2): 125–33. doi:10.1093/fampra/cms059. PMID 22997224.
- Jefferson T, Jones MA, Doshi P, et al. (2012). "Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children". In Jefferson, Tom. Cochrane Database Syst Rev 1: CD008965. doi:10.1002/14651858.CD008965.pub3. PMID 22258996.
- Jefferson, T; Jones, MA; Doshi, P; Del Mar, CB; Heneghan, CJ; Hama, R; Thompson, MJ (Jan 18, 2012). "Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children". In Jefferson, Tom. Cochrane database of systematic reviews (Online) 1: CD008965. doi:10.1002/14651858.CD008965.pub3. PMID 22258996.
- Wang K, Shun-Shin M, Gill P, Perera R, Harnden A (2012). "Neuraminidase inhibitors for preventing and treating influenza in children (published trials only)". In Harnden, Anthony. Cochrane Database Syst Rev 4: CD002744. doi:10.1002/14651858.CD002744.pub4. PMID 22513907.
- "Update on oseltamivir resistance to influenza H1N1 (2009) viruses". World Health Organization (WHO). December 15, 2010. Retrieved December 30, 2010.
- De Jong, D.; Tran, T.; Truong, K.; Vo, H.; Smith, J.; Nguyen, C.; Bach, C.; Phan, Q.; Do, H.; Guan, Y.; Peiris, J. S. M.; Tran, T. T.; Farrar, J. (Dec 2005). "Oseltamivir resistance during treatment of influenza A (H5N1) infection". The New England Journal of Medicine 353 (25): 2667–2672. doi:10.1056/NEJMoa054512. ISSN 0028-4793. PMID 16371632.
- Ward, P.; Small, I.; Smith, J.; Suter, P.; Dutkowski, R. (Feb 2005). "Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic" (Free full text). The Journal of antimicrobial chemotherapy 55 (Suppl 1): i5–i21. doi:10.1093/jac/dki018. ISSN 0305-7453. PMID 15709056.
- Tamiflu (oseltamivir phosphate) Information U.S. Food and Drug Administration (FDA)
- Godlee F (2012). "Open letter to Roche about oseltamivir trial data". BMJ 345: e7305. doi:10.1136/bmj.e7305. PMID 23109484.
- Fiona Godlee (2009). "We want raw data, now". BMJ 339: b5405. doi:10.1136/bmj.b5405.
- Hernán MA, Lipsitch M (August 2011). "Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: a meta-analysis of eleven randomized clinical trials". Clin. Infect. Dis. 53 (3): 277–9. doi:10.1093/cid/cir400. PMC 3137795. PMID 21677258.
- Tamiflu Prescribing Information
- Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
- Waknine, Yael (2006). "Tamiflu May Be Linked to Risk for Self-Injury and Delirium". Medscape. Retrieved 17 May 2008.
- Parry, Richard Lloyd (March 21, 2007). "Japan issues Tamiflu warning after child deaths". The Times (London). Retrieved 2009-05-05.
- "Japan to keep stockpiling Tamiflu". Sydney Morning Herald. Reuters. 2007-03-28. Retrieved 2009-07-29.
- "Japan finds 128 abnormal cases in Tamiflu probe". Forbes. AFX News Limited. 2007-05-04. Archived from the original on 2011-06-04. Retrieved 2009-07-29.
- Russell, Sabin (2005-11-15). "Japan links Tamiflu to 2 teen suicides". San Francisco Chronicle. Retrieved 2009-07-29.
- Fuyuno, I. . (Mar 2007). "Tamiflu side effects come under scrutiny". Nature 446 (7134): 358–359. Bibcode:2007Natur.446..358F. doi:10.1038/446358a. ISSN 0028-0836. PMID 17377552.
- "Tamiflu linked to abnormal behaviour". Sydney Morning Herald. Associated Press. 2009-04-20. Retrieved 2009-07-29.
- "Flu Drug Tamiflu May Cause Odd Behavior in Children". Forbes. 2006-11-13.[dead link]
- Pediatric Advisory Committee. 2005. "Pediatric safety update for Tamiflu". U.S. Food and Drug Administration (FDA)
- "FDA adds 'abnormal behavior' precaution to Tamiflu label". USA Today. Associated Press. 2006-11-14. Retrieved 2009-07-29.
- "SKorea suspends Tamiflu use for young people - official". Forbes. AFX News Limited. 2007-04-05. Archived from the original on 2011-06-04. Retrieved 2009-07-29.
- Jefferson T, Jones M, Doshi P, Del Mar C (2009). "Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis". BMJ 339: b5106. doi:10.1136/bmj.b5106. PMC 2790574. PMID 19995812.
- Godlee, F.; Clarke, M. (2009). "Why don't we have all the evidence on oseltamivir?". BMJ 339: b5351. doi:10.1136/bmj.b5351. PMID 19995815.
- Soundararajan V; Tharakaraman K, Raman R, Raguram S, Shriver Z, Sasisekharan V, Sasisekharan R (9 June 2009). "Extrapolating from sequence--the 2009 H1N1 'swine' influenza virus". Nature Biotechnology 27 (6): 510–3. doi:10.1038/nbt0609-510. PMID 19513050.
- Kiso, M.; Mitamura, K.; Sakai-Tagawa, Y.; Shiraishi, K.; Kawakami, C.; Kimura, K.; Hayden, F.; Sugaya, N.; Kawaoka, Y. (2004). "Resistant influenza a viruses in children treated with oseltamivir: descriptive study". The Lancet 364 (9436): 759–765. doi:10.1016/S0140-6736(04)16934-1.
- Hatakeyama, S.; Sugaya, N.; Ito, M.; Yamazaki, M.; Ichikawa, M.; Kimura, K.; Kiso, M.; Shimizu, H.; Kawakami, C.; Koike, K.; Mitamura, K.; Kawaoka, Y. (Apr 2007). "Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors" (Free full text). Journal of the American Medical Association 297 (13): 1435–1442. doi:10.1001/jama.297.13.1435. ISSN 0098-7484. PMID 17405969.
- Le, M.; Kiso, M.; Someya, K.; Sakai, T.; Nguyen, H.; Nguyen, H.; Pham, D.; Ngyen, H.; Yamada, S.; Muramoto, Y. et al. (Oct 2005). "Avian flu: isolation of drug-resistant H5N1 virus". Nature 437 (7062): 1108. Bibcode:2005Natur.437.1108L. doi:10.1038/4371108a. ISSN 0028-0836. PMID 16228009.
- "WHO intercountry-consultation. Influenza A/H5N1 in humans in Asia. Manila, Philippines, 6–7 May 2005". World Health Organization. May 2005.
- Moscona, A. . (Dec 2005). "Oseltamivir resistance--disabling our influenza defenses". The New England Journal of Medicine 353 (25): 2633–2636. doi:10.1056/NEJMp058291. ISSN 0028-4793. PMID 16371626.
- Collins PJ, Haire LF, Lin YP, Liu J, Russell RJ, Walker PA, Skehel JJ, Martin SR, Hay AJ, Gamblin SJ (June 2008). "Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants". Nature 453 (7199): 1258–61. Bibcode:2008Natur.453.1258C. doi:10.1038/nature06956. PMID 18480754.
- Garcia-Sosa AT, Sild S, Maran U (October 2008). "Design of multi-binding-site inhibitors, ligand efficiency, and consensus screening of avian influenza H5N1 wild-type neuraminidase and of the oseltamivir-resistant H274Y variant". J. Chem. Inf. Model. 48 (10): 2074–80. doi:10.1021/ci800242z. PMID 18847186.
- Avian Flu Drugs: Patent Questions, WIPO Magazine, April 2006
- Schwartz, Nelson (October 31, 2005). "Rumsfeld's growing stake in Tamiflu: Defense Secretary, ex-chairman of flu treatment rights holder, sees portfolio value growing". Fortune. Retrieved November 28, 2005.
- "Roche to suspend Tamiflu shipments to US private sector". Forbes. AFX News Limited. 2005-10-27. Archived from the original on 2009-05-13. Retrieved 2009-07-29.
- "Man dies of bird flu in Vietnam". Gulf Times. 2005-11-09. Retrieved 2009-09-27.
- Tran Van Minh (2005-11-09). "Vietnam to produce generic bird-flu drug". The Washington Post. Associated Press. Retrieved 2009-07-29.
- Le Thang Long (2005-11-10). "Roche lets Vietnam make Tamiflu". The Standard. Retrieved 2009-07-29.
- Shannon Brownlee and Jeanne Lenzer (November 2009) "Does the Vaccine Matter?", The Atlantic
- "China-made Tamiflu approved for production". People's Daily. 2006-06-13. Retrieved 2009-07-29.
- McCoy, Michael (2006-03-20). "Making Tamiflu". Chemical & Engineering News. Retrieved 2009-07-29.
- "WHO puts Tamiflu maker on alert after suspected human-to-human transmission". Medical News Today. 2006-05-27. Retrieved 2009-07-29.
- "Cipla's anti-flu drug gets nod". Times of India. 2009-05-14. Retrieved 2009-07-29.
- "Tamiflu readily available for 2006/2007 influenza season" (Press release). Roche. 2006-10-02. Retrieved 2009-07-29.
- "Roche boosts Tamiflu production; CDC cites signs of hoarding". CIDRAP. 2006-03-16. Retrieved 2009-07-29.
- "Roche update on Tamiflu for pandemic influenza preparedness" (Press release). 2006-03-16. Retrieved 2009-07-29.
- "Doctors test double Tamiflu dose to cut H5N1 deaths". Retuers. 2007-03-28. Retrieved 2009-07-29.
- Bradley, D. . (Dec 2005). "Star role for bacteria in controlling flu pandemic?". Nature reviews. Drug discovery 4 (12): 945–946. doi:10.1038/nrd1917. ISSN 1474-1776. PMID 16370070.
- Krämer, M.; Bongaerts, J.; Bovenberg, R.; Kremer, S.; Müller, U.; Orf, S.; Wubbolts, M.; Raeven, L. (2003). "Metabolic engineering for microbial production of shikimic acid". Metabolic Engineering 5 (4): 277–283. doi:10.1016/j.ymben.2003.09.001. PMID 14642355.
- Johansson, L.; Lindskog, A.; Silfversparre, G.; Cimander, C.; Nielsen, K. F.; Lidén, G. (Dec 2005). "Shikimic acid production by a modified strain of E. Coli (W3110.shik1) under phosphate-limited and carbon-limited conditions". Biotechnology and Bioengineering 92 (5): 541–552. doi:10.1002/bit.20546. ISSN 0006-3592. PMID 16240440.
- Guo, J.; Frost, W. (May 2004). "Synthesis of aminoshikimic acid". Organic Letters 6 (10): 1585–1588. doi:10.1021/ol049666e. ISSN 1523-7060. PMID 15128242.
- Abrecht, S.; Harrington, P.; Iding, H.; Karpf, M.; Trussardi, R.; Wirz, B.; Zutter, U. (2004). "The Synthetic Development of the Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu®): A Challenge for Synthesis & Process Research". CHIMIA International Journal for Chemistry 58 (9): 621. doi:10.2533/000942904777677605.
- US 7977077 "Synthesis of oseltamivir carboxylates"
- Rudolf, M.; Bernstein, B. (Apr 2004). "Counterfeit drugs". The New England Journal of Medicine 350 (14): 1384–1386. doi:10.1056/NEJMp038231. ISSN 0028-4793. PMID 15070787.
- Savigny, M. R.; MacIntire, D. K. (2010). "Use of oseltamivir in the treatment of canine parvoviral enteritis". Journal of Veterinary Emergency and Critical Care 20 (1): 132–142. doi:10.1111/j.1476-4431.2009.00404.x. PMID 20230441.
- Macintire, Douglass K. (2006). "Treatment of Parvoviral Enteritis". Proceedings of the Western Veterinary Conference. Retrieved 2007-06-09.
- Karpf, Martin, Martin; Trussardi, René (February 24, 2001). "New, Azide-Free Transformation of Epoxides into 1,2-Diamino Compounds: Synthesis of the Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu)". Journal of Organic Chemistry 66 (6): 2044–2051. doi:10.1021/jo005702l. PMID 11300898.
- Tamiflu Prescribing InformationU.S. Food and Drug Administration (FDA)
- Pollack, Andrew (November 5, 2005). "Is Bird Flu Drug Really So Vexing? Debating the Difficulty of Tamiflu". The New York Times.
- "Avian influenza virus infections in humans". Chest 129 (1): 156–168. January 2006. doi:10.1378/chest.129.1.156. PMID 16424427.
- Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.; Chapman, H. H.; Kelly, D. E.; Lew, W.; Louie, M. S.; McGee, L. R.; Prisbe, E. J.; Schultze, L. M.; Yu, R. H.; Zhang, L. (1998). "Practical Total Synthesis of the Anti-Influenza Drug GS-4104". The Journal of Organic Chemistry 63 (13): 4545–4550. doi:10.1021/jo980330q.
- Karpf, T. R.; Trussardi, R. (March 2001). "New, azide-free transformation of epoxides into 1,2-diamino compounds: synthesis of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu)". J. Org. Chem. 66 (6): 2044–2051. doi:10.1021/jo005702l. PMID 11300898.
- Abrecht, S.; Harrington, P.; Iding, H.; Karpf, M.; Trussardi, R.; Wirz, B.; Zutter, U. (2004). "The Synthetic Development of the Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu®): A Challenge for Synthesis & Process Research". CHIMIA International Journal for Chemistry 58 (9): 621. doi:10.2533/000942904777677605.
- Yeung, H. S.; Hong, S.; Corey, E. J. (May 2006). "A short enantioselective pathway for the synthesis of the anti-influenza neuramidase inhibitor oseltamivir from 1,3-butadiene and acrylic acid". J. Am. Chem. Soc. 128 (19): 6310–6311. doi:10.1021/ja0616433. PMID 16683783.
- Tse, N.; Cederbaum, S.; Glaspy, J. A. (Oct 1991). "Hyperammonemia following allogeneic bone marrow transplantation" (Free full text). American journal of hematology 38 (2): 140–141. doi:10.1002/ajh.2830380213. ISSN 0361-8609. PMID 1951305.
|Wikimedia Commons has media related to:|
- Official website
- MedlinePlus Drug Information: oseltamivir (systemic) –Last Revised - 05/01/2009 Advice for the Patient
- Pharmasquare – Tamiflu Mode of Action – Flash animation showing the mode of action of oseltamivir
- FDA information page on oseltamivir
- Flu Drugs FAQ – U.S. National Institute of Allergy and Infectious Diseases
- Reto U. Schneider: The race to develop GS4104 - A comprehensive feature story about the development of Tamiflu published in January 2004 in NZZ-Folio, the magazine of the daily Neue Zürcher Zeitung in Switzerland (translated from German).