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Encyclopedia > Oseltamivir
Oseltamivir
Systematic (IUPAC) name
(3R,4R,5S)-4-acetylamino-5-amino-
3-(1-ethylpropoxy)-1-cyclohexene-
1-carboxylic acid ethyl ester
Identifiers
CAS number 196618-13-0
ATC code J05AH02
PubChem 65028
DrugBank APRD01148
Chemical data
Formula C16H28N2O4 
Mol. mass 312.4 g/mol
Pharmacokinetic data
Bioavailability 75%
Metabolism hepatic, to GS4071
Half life 6–10 hours
Excretion renal (GS4071)
Therapeutic considerations
Pregnancy cat.

B1 (Australia), C (U.S.) Image File history File links Size of this preview: 708 × 600 pixel Image in higher resolution (1100 × 932 pixel, file size: 40 KB, MIME type: image/png) File links The following pages on the English Wikipedia link to this file (pages on other projects are not listed): Oseltamivir ... Image File history File links Size of this preview: 722 × 599 pixel Image in higher resolution (1100 × 913 pixel, file size: 195 KB, MIME type: image/png) File links The following pages on the English Wikipedia link to this file (pages on other projects are not listed): Oseltamivir Oseltamivir total... IUPAC nomenclature is a system of naming chemical compounds and of describing the science of chemistry in general. ... CAS registry numbers are unique numerical identifiers for chemical compounds, polymers, biological sequences, mixtures and alloys. ... The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs. ... A section of the Anatomical Therapeutic Chemical Classification System. ... PubChem is a database of chemical molecules. ... The DrugBank database available at the University of Alberta is a unique bioinformatics and cheminformatics resource that combines detailed drug (i. ... This article does not cite its references or sources. ... General Name, Symbol, Number carbon, C, 6 Chemical series nonmetals Group, Period, Block 14, 2, p Appearance black (graphite) colorless (diamond) Standard atomic weight 12. ... General Name, Symbol, Number hydrogen, H, 1 Chemical series nonmetals Group, Period, Block 1, 1, s Appearance colorless Atomic mass 1. ... General Name, Symbol, Number nitrogen, N, 7 Chemical series nonmetals Group, Period, Block 15, 2, p Appearance colorless gas Standard atomic weight 14. ... General Name, Symbol, Number oxygen, O, 8 Chemical series nonmetals, chalcogens Group, Period, Block 16, 2, p Appearance colorless (gas) very pale blue (liquid) Standard atomic weight 15. ... The molecular mass (abbreviated MM) of a substance, formerly also called molecular weight and abbreviated as MW, is the mass of one molecule of that substance, relative to the unified atomic mass unit u (equal to 1/12 the mass of one atom of carbon-12). ... In pharmacology, bioavailability is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. ... Drug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. ... The liver is an organ in vertebrates including humans. ... It has been suggested that Effective half-life be merged into this article or section. ... Excretion is the process of eliminating waste products of metabolism and other materials that are of no use. ... Kidneys viewed from behind with spine removed The kidneys are bean-shaped excretory organs in vertebrates. ... The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. ... For other uses, see United States (disambiguation) and US (disambiguation). ...

Legal status

Prescription Only (S4)(AU) POM(UK) -only(US) The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. ... The Standard for the Uniform Scheduling of Drugs and Poisons, abbreviated SUSDP, is a document used in the regulation of drugs and poisons in Australia. ... Anthem Advance Australia Fair Royal anthem: God Save the Queen Capital Canberra Largest city Sydney Official languages English (de facto 1) Government Federal constitutional monarchy and parliamentary democracy  -  Queen Elizabeth II  -  Governor-General Michael Jeffery  -  Prime Minister John Howard Independence from the United Kingdom   -  Constitution 1 January 1901   -  Statute of... A prescription drug is a licensed medicine that is regulated by legislation to require a prescription before it can be obtained. ... A prescription drug is a licensed medicine that is regulated by legislation to require a prescription before it can be obtained. ... Motto: (Out Of Many, One) (traditional) In God We Trust (1956 to date) Anthem: The Star-Spangled Banner Capital Washington D.C. Largest city New York City None at federal level (English de facto) Government Federal constitutional republic  - President George Walker Bush (R)  - Vice President Dick Cheney (R) Independence from...

Routes oral

Oseltamivir (INN) (IPA: [ɒsɛlˈtæmɪvir]) is an antiviral drug that is used in the treatment and prophylaxis of both Influenzavirus A and Influenzavirus B. Like zanamivir, oseltamivir is a neuraminidase inhibitor. It acts as a transition-state analogue inhibitor of influenza neuraminidase, preventing new viruses from emerging from infected cells. In pharmacology and toxicology, a route of administration is the path by which a drug, fluid, poison or other substance is brought into contact with the body 1. ... An International Nonproprietary Name (INN) is the official non-proprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization. ... Articles with similar titles include the NATO phonetic alphabet, which has also informally been called the “International Phonetic Alphabet”. For information on how to read IPA transcriptions of English words, see IPA chart for English. ... Antiviral drugs are a class of medication used specifically for treating viral infections. ... Prophylaxis refers to any medical or public health procedure whose purpose is to prevent, rather than treat or cure, disease. ... Genera Influenzavirus A Influenzavirus B Influenzavirus C Isavirus Thogotovirus Influenzavirus A is a genus of a family of viruses called Orthomyxoviridae in virus classification. ... Influenzavirus B is a genus in the virus family Orthomyxoviridae. ... Zanamivir is a neuraminidase inhibitor used in the treatment of and prophylaxis of both influenza A and influenza B. Zanamivir was the first neuraminidase inhibitor commercially developed. ... Neuraminidase inhibitors are a class of antiviral drugs, whose mode of action relies on blocking the function of viral neuraminidase protein, thus preventing the virus from budding from the host cell. ... The transition state of a chemical reaction is a particular configuration along the reaction coordinate. ... Neuraminidase is a glycoside hydrolase enzyme (EC 3. ...


Oseltamivir was the first orally active neuraminidase inhibitor commercially developed. It is a prodrug, which is hydrolysed hepatically to the active metabolite, the free carboxylate of oseltamivir (GS4071). It was developed by Gilead Sciences and is currently marketed by Hoffmann-La Roche (Roche) under the trade name Tamiflu. In Japan, it is marketed by Chugai Pharmaceutical Co., which is more than 50% owned by Roche. Oseltamivir is generally available by prescription only. A prodrug is a pharmacological substance (drug) which is administered in an inactive (or significantly less active) form. ... Hydrolysis is a chemical reaction or process in which a chemical compound reacts with water. ... Structure of a carboxylic acid The 3D structure of the carboxyl group A space-filling model of the carboxyl group Carboxylic acids are organic acids characterized by the presence of a carboxyl group, which has the formula -C(=O)OH, usually written -COOH or -CO2H. [1] Carboxylic acids are Bronsted... Gilead Sciences NASDAQ: GILD is a biopharmaceutical company that discovers, develops and commercializes therapeutics to advance the care of patients suffering from life-threatening diseases, principally HIV, hepatitis B and influenza. ... Hoffmann-La Roche, Ltd. ... A trade name, also known as a trading name or a business name, is the legal name of a business, or the name which a business trades under for commercial purposes. ...


Roche estimates that 50 million people have been treated with oseltamivir.[5] The majority of these have been in Japan, where an estimated 35 million have been treated.[6]


With increasing fears about the potential for a new influenza pandemic, oseltamivir has received substantial media attention. Governments, corporations, and even some private individuals are stockpiling the drug. Production is currently sufficient to meet the demand for seasonal influenza and for government stockpiling. It is possible that shortages could re-emerge in the event of an actual influenza pandemic.

Contents

Clinical use

Indications and dosage

Oseltamivir is indicated for the treatment of infections due to influenza A and B virus in people at least one year of age, and prevention of influenza in people at least one year or older. The usual adult dosage for treatment of influenza is 75 mg twice daily for 5 days, beginning within 2 days of the appearance of symptoms and with decreased doses for children and patients with renal impairment. Oseltamivir may be given as a preventive measure either during a community outbreak or following close contact with an infected individual. Standard prophylactic 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. (Roche, 2005; Rossi, 2006)


Use and dosage for avian influenza

After following WHO protocols in treating 41 victims of the H5N1 bird flu virus (19% of the world-wide cases of bird flu reported to date), Nguyen Tuong Van, MD, who runs the intensive care unit of the Center for Tropical Diseases in Hanoi, Vietnam concluded that Tamiflu, the drug most widely stockpiled around the world to combat a potential bird flu pandemic, is "useless." According to this article, the WHO confirmed Van's experience stating that Tamiflu has not been "widely successful in human patients", but speculated the drug has not been administered until late in the disease in many Asian countries.


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 (de Jong et al. 2005). Accordingly, it has been suggested that higher doses and longer durations of therapy should be used for treatment of patients with the H5N1 virus (de Jong et al. 2005, Ward et al. 2005). Influenza A virus subtype H5N1, also known as A(H5N1) or simply H5N1, is a subtype of the Influenza A virus which can cause illness in humans and many other animal species. ... Avian influenza (also known as bird flu, avian flu, influenzavirus A flu, type A flu, or genus A flu) is a flu (influenza) due to a type of influenza virus that is hosted by birds, but may infect several species of mammals. ...


Clinical trials for an increased dosage were set to begin in by May 2007. All avian influenza cases in Indonesia, Thailand, and Vietnam will be inducted into the trial. The trial will also include 100 cases of severe seasonal influenza from each of those countries, plus the United States. Half of cases will receive the current standard dosage, and half will receive a double dosage, but for the standard length of time.[7][8]


Chokephaibulkit et al recommend the use of oseltamivir for children with avian influenza, based on experience with one patient.


Co-administration with probenecid

It has been suggested that co-administration of oseltamivir with probenecid could extend the limited supply of oseltamivir. Probenecid reduces renal excretion of the active metabolite of oseltamivir. One study showed that 500 mg of probenicid given every six hours doubled both the peak plasma concentration (Cmax) and the half-life of oseltamivir, increasing overall systemic exposure (AUC) by 2.5-fold. (Hill et al., 2002) Although the evidence for this interaction comes from a study by Roche, it was publicised only in October 2005 by a doctor who had reviewed the data (Butler, 2005). Probenecid was used in similar fashion during World War II to extend limited supplies of penicillin. It is still used to increase penicillin concentrations in serious infections. Probenecid is a uricosuric drug, primarily used in treating gout or hyperuricemia, that increases uric acid removal in the urine. ... Kidneys viewed from behind with spine removed The kidneys are bean-shaped excretory organs in vertebrates. ... The elimination half-life of a drug (or any xenobiotic agent) refers to the timecourse necessary for the quantity of the xenobiotic agent in the body (or plasma concentration) to be reduced to half of its original level through various elimination processes. ... area under the curve: AUC means area under the curve. This is the area under the concentration time curve. ... Penicillin nucleus Penicillin (sometimes abbreviated PCN) refers to a group of β-lactam antibiotics used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms. ...


Dosage forms

Oseltamivir is marketed by Roche 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 12 mg/mL). Image File history File linksMetadata Tamiflu. ...


Adverse effects

Common adverse drug reactions (ADRs) associated with oseltamivir therapy 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. (Rossi, 2006) An adverse drug reaction (abbreviated ADR) is a term to describe the unwanted, negative consequences sometimes associated with the use of medications. ... Hepatitis (plural hepatitides) implies injury to liver characterised by presence of inflammatory cells in the liver tissue. ... The liver is an organ present in vertebrates and some other animals. ... Ribbon diagram of the enzyme TIM, surrounded by the space-filling model of the protein. ... }} In medicine, anaphylaxis is a severe and rapid multi-system allergic reaction. ... Stevens-Johnson syndrome (SJS) is a severe and life-threatening condition. ...


Various other ADRs have been reported in postmarketing surveillance including: toxic epidermal necrolysis, cardiac arrhythmia, seizure, confusion, aggravation of diabetes, and haemorrhagic colitis. Toxic epidermal necrolysis is a life-threatening and usually drug-induced dermatological condition that occurs more often in women than in men. ... Cardiac arrhythmia is a group of conditions in which the electrical activity of the heart is irregular or is faster or slower than normal. ... To meet Wikipedias quality standards, this article or section may require cleanup. ... Colitis is a digestive disease characterized by inflammation of the colon. ...


Neurological effects

There are concerns that oseltamivir may cause dangerous psychological side effects in some people. This stems from cases in Japan, where the drug is most heavily prescribed. Concern has focused on teenagers, but problems have also been reported in children and adults.


In March 2007, Japan's Health Ministry warned that oseltamivir should not be given to children aged 10 to 19. [9] 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. Neurology is a branch of medicine dealing with disorders of the central and peripheral nervous systems. ... Psychology (ancient Greek: psyche = soul and logos = word) is the study of mind, thought, and behaviour. ... A hallucination is a sensory perception experienced in the absence of an external stimulus, as distinct from an illusion, which is a misperception of an external stimulus. ...


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 fallen from buildings after taking oseltamivir, and one 17-year-old died after he jumped in front of a truck.[10][11][12] 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 as a result.[13] (For more on Japan, also see: [1] [2])


In November 2006, the United States Food and Drug Administration (FDA) amending the warning label to include the possible side effects of delirium, hallucinations, or other related behavior.[3] 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). [4] The change to a more cautionary stance was attributed to 103 new reports that 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. [14] FDA logo The Food and Drug Administration (FDA) is an agency of the United States Department of Health and Human Services and is responsible for regulating food, dietary supplements, drugs, biological medical products, blood products, medical devices, radiation-emitting devices, veterinary products, and cosmetics in the United States. ... “Delirious” redirects here. ...


In October 2006, Shumpei Yokota, a professor of pediatrics at Yokahama City University, released the results of research involving around 2,800 children which found no difference in the behavior between those who took oseltamivir and those who did not. A media source notes that Chugai Pharmaceutical Co. (which produces Tamiflu in Japan) gave Yokota's department 10 million yen ($85,000) over five years.[15][16]


Roche points out that Tamiflu has been used to treat 50 million people since 1999, and states that influenza may itself cause psychological problems.[17][18]


In March 2007, the European Medicines Agency said that the benefits of oseltamivir outweighed the costs, but that it would closely monitor reports from Japan. [19]


In April 2007, South Korea issued a safety warning against prescribing tamiflu to teenagers except in special cases.[20]


Mode of action

Oseltamivir is a neuraminidase inhibitor. By blocking the activity of the neuraminidase, Oseltamivir prevents new viral particles from being released by infected cells. Neuraminidase inhibitors are a class of antiviral drugs, whose mode of action relies on blocking the function of viral neuraminidase protein, thus preventing the virus from budding from the host cell. ...


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). Antibiotic resistance is the ability of a micro-organism to withstand the effects of an antibiotic. ... Amantadine, 1-aminoadamantane, is an antiviral drug that was approved by the FDA in 1976 for the treatment of influenza type A in adults. ... Rimantadine (systematic name 1-(1-aminoethyl)adamantane) is an orally administered medicine used to treat, and in rare cases prevent, Influenzavirus A infection. ... 2004 : January - February - March - April - May - June - July - August - September - October - November - December See also: July 2004 in sports Deaths in July • 31 David B. Haight • 29 Francis Crick • 29 Nafisa Joseph • 23 Joe Cahill • 23 Mehmood • 23 Illinois Jacquet • 23 Carlos Paredes... Phenylalanine is one of the standard amino acids. ... Neuraminidase is a glycoside hydrolase enzyme (EC 3. ...


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. It has been suggested that this article or section be merged into mutation. ... H3N2 is a subtype of the species Influenza A virus (sometimes called bird flu virus). ... H1N1 is a subtype of the species Influenza A virus (sometimes called bird flu virus). ...


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 (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. (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 or bird-to-human transmission. Neuraminidase is a glycoside hydrolase enzyme (EC 3. ... Neuraminidase is a glycoside hydrolase enzyme (EC 3. ... Zanamivir is a neuraminidase inhibitor used in the treatment of and prophylaxis of both influenza A and influenza B. Zanamivir was the first neuraminidase inhibitor commercially developed. ...


In 2007, Japanese investigators detected neuraminidase-resistant Influenza B virus strains in individuals who had not been treated with these drugs. The prevalence was 1.7%.[5]


Pandemic fears

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, United States and Australia – stockpiled quantities of oseltamivir in preparation for a possible pandemic. Though large, the quantities stockpiled would not have been sufficient to protect the entire population of these countries. In epidemiology, an epidemic (from [[Latin language] epi- upon + demos people) is a disease that appears as new cases in a given human population, during a given period, at a rate that substantially exceeds what is expected, based on recent experience (the number of new cases in the population during... Location of Southeast Asia Southeast Asia is a subregion of Asia. ... 2005 (MMV) was a common year starting on Saturday of the Gregorian calendar. ... A pandemic (from Greek παν pan all + δήμος demos people) is an epidemic (an outbreak of an infectious disease) that spreads across a large region (example a continent), or even worldwide. ...

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 authorise supply from generic companies, subject to remuneration to patent owners to address public health problems, including emergencies, although Roche has announced its intention to remain the sole supplier of the drug. Cipla argues that it can legally sell oseltamivir to India and 49 other developing countries, possibly as early as January 2006. Also in October, it was announced that Roche was in discussions with four generic drug manufacturers about the possibility of issuing sublicenses to increase production. Image File history File links WikiNews-Logo. ... Wikinews is a free-content news source and a project of the Wikimedia Foundation. ... Cipla is an Indian pharmaceutical company, best-known for manufacturing cheap anti-AIDS drugs. ... A patent is a set of exclusive rights granted by a state to a patentee (the inventor or assignee) for a fixed period of time in exchange for the regulated, public disclosure of certain details of a device, method, process or composition of matter (substance) (known as an invention) which... A compulsory license is a license to use a patent, copyright, or other exclusive right that a government forces the holder to grant to others. ... It has been suggested that Underdevelopment be merged into this article or section. ...


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. [21][22][23] 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[24].


On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir[25]. The week before, Thai authorities said they would begin producing generic oseltamivir, claiming that Roche had not patented Tamiflu in Thailand[26]. The first Thai generic oseltamivir was produced in February 2006 and are to be available to the public in July 2006[27].


In December 2005, Roche also signed a sublicense for complete oseltamivir production with China's Shanghai Pharmaceuticals, and by March 2006 a sublicense had also been granted to India's Hetero [28][29]. In June 2006, the Chinese government gave Shanghai Pharmaceuticals permission to proceed, based upon tests of the domestic production. The company said it planned to market the drug by the end of the month.[30][31]


In late May 2006, the World Health Organization 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 [32][33]. The World Health Organization (WHO) is a specialized agency of the United Nations that acts as a coordinating authority on international public health, headquartered in Geneva, Switzerland. ...


U.S. Government policy and oseltamivir

In November, 2005, U.S. president George W. Bush requested that Congress fund $7.1 billion in emergency spending for flu pandemic preparedness (the Senate had already passed an $8.1 billion bill)[34]. Bush's plan included $1.4 billion for government purchases of antiviral drugs[35].


Some commentators (e.g., [36]) question the motives of the U.S. government's endorsement and planned purchase of oseltamivir, noting Secretary of Defense Donald Rumsfeld's close ties to Gilead Sciences, rightsholder to the oseltamivir patent. Rumsfeld is a former chairman of Gilead, and federal disclosure forms indicate that he owns between USD$5 million and USD$25 million in Gilead stock (Schwartz 2005 [37]). The rise in Gilead's share prices from USD$35 to USD$57 per share will have added between USD$2.5 million to USD$15.5 million to Rumsfeld's net worth. Donald Henry Rumsfeld (born July 9, 1932) is a U.S. politician and businessman, who was the 13th Secretary of Defense under President Gerald Ford from 1975–1977, and the 21st Secretary of Defense under President George W. Bush from 2001–2006. ... Gilead Sciences NASDAQ: GILD is a biopharmaceutical company that discovers, develops and commercializes therapeutics to advance the care of patients suffering from life-threatening diseases, principally HIV, hepatitis B and influenza. ...


On the other hand, at least one Democratic Senator has criticized Bush for not planning to buy enough antiviral drugs [38].


Personal stockpiling of oseltamivir

A short supply of oseltamivir prompted some individuals to stockpile the drug. Several American states, including Massachusetts and Colorado, issued advisories strongly discouraging this practice. Production has now caught up with current demand (see below), so some (but not all) of the practical and ethical issues surrounding personal stockpiling are reduced. It is possible that shortages could again be encountered if a global influenza pandemic actually arose.


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 et al., 2005)


Another 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 as to whether affluent people or nations should have preferred access to antiviral medications. Illegal importation may 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. [39] Corporate may refer to either A corporation, a type of legal entity, often formed to conduct business Corporate (film), a 2006 Bollywood film starring Bipasha Basu. ...


A third 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 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 counterfeit Tamiflu appearing outside of the United States: incorrectly-labelled tablets found in Holland, which contained only Vitamin C and lactose. However, sophisticated criminals could produce convincing fake packaging in the future. [40][41]


Finally, 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.


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.[42] Individual stockpiling could bring market forces to play, increasing production capacity and allowing the total supply on hand to be higher.


Veterinary use

Oseltamivir 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 [43] and canine flu [44]is ongoing, but many shelters and rescue groups have reported great success employing oseltamivir in the early stages of these illnesses. Canine parvovirus (CPV) is a contagious virus affecting dogs. ... Feline panleukopenia, more commonly known as feline distemper, is a viral infection affecting cats caused by feline parvovirus, a close relative of canine parvovirus. ... Kennel cough or tracheobronchitis is a highly contagious canine illness characterized by inflammation of the upper respiratory system. ... Canine influenza or dog flu refers to varieties of influenzavirus A that affect dogs. ... Dog at a no-kill animal shelter in Washington, Iowa An animal shelter is a facility that houses homeless, lost or abandoned animals; primarily a large variety of dogs and cats. ... A rescue group or rescue organization takes unwanted or abused pets and attempts to find new, caring homes for them. ...


Chemical synthesis

The current production method includes two reaction steps with potentially hazardous azides. A reported azide-free Roche synthesis of tamiflu is summarised graphically below: Oseltamivir total synthesis concerns the total synthesis of the antiinfluenza drug oseltamivir marketed by Hoffmann-La Roche under the trade name Tamiflu. ... An azide is the N3- anion, the anion of hydrazoic acid or a reactive group in organic chemistry where a carbon substituent is attached as RN3. ...

To date two alternative synthetic routes have been published. Image File history File links Download high resolution version (695x1015, 39 KB) Summary redrawn by me from references Licensing Patented Material is not for commercial uses. ...


Production shortage/shikimic acid

In early 2005, Roche announced a production shortage. (See Pandemic Fears, above). However, 2006, Roche said that production was about to reach 400-million treatment courses annually, that "capacity was well in excess of total government orders placed to date," and that "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 that 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. [45][46][47]


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 hopes that it would cut H5N1 influenza virus death rate.[48] 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 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. It is also produced in Lang Son province, Vietnam. 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 oseltamivir 75 mg capsules. Ninety percent of the harvest is already used by Roche in making oseltamivir. Shikimic acid, more commonly known as its anionic form shikimate, is an important biochemical intermediate in plants and microorganisms. ... Binomial name Illicium verum Hook. ... This article or section does not adequately cite its references or sources. ...


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 sweetgum and ginkgo trees. In addition, quinic acid, derived from the bark of the cinchona tree of the Democratic Republic of the Congo, is a potential alternative base material for the production of oseltamivir. Shikimic acid, more commonly known as its anionic form shikimate, is an important biochemical intermediate in plants and microorganisms. ... Binomial name Illicium verum Hook. ... Species Liquidambar formosana Liquidambar orientalis Liquidambar styraciflua The sweetgums Liquidambar are a genus in the witch-hazel family Hamamelidaceae, with three species of large deciduous trees, 25-40m tall, with palmately lobed leaves: Liquidambar formosana - Chinese Sweetgum (central & southern China, Taiwan). ... Binomial name Ginkgo biloba L. The Ginkgo (Ginkgo biloba), frequently misspelled as Gingko, and sometimes known as the Maidenhair Tree, is a unique tree with no close living relatives. ... Quinic acid, C7H12O6 is a crystalline acid obtained from cinchona bark, coffee beans, and other plant products and made synthetically by hydrolysis of chlorogenic acid. ... Species See text Cinchona L., is the name of a genus in Rubiaceae family, large evergreens that can grow over 10 metres tall. ...


However, as is clear by the multistep synthesis shown above, 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).


Canadian generic drug company Apotex is attempting to modify Oseletamivir to use a synthetic alternative to shikimic acid. Apotex is a Canadian pharmaceutical corporation. ...


References

  1. ^ Other media reports on neurological side effects in Japan: [1][2][3][4]
  2. ^ "Links to Tamiflu-Related Incidents in The Japan Times", 2006-11-13. 
  3. ^ "Flu Drug Tamiflu May Cause Odd Behavior in Children", Forbes, 2006-11-13. 
  4. ^ Pediatric Advisory Committee. 2005. Pediatric safety update for Tamiflu. Rockville (MD): U.S. Food and Drug Administration.
  5. ^ H. Shuji; S. Norio; I. Mutsumi; Y. Masahiko; I. Masataka; K. Kazuhiro; K. Maki; S. Hideaki; K. Chiharu; K. Kazuhiko; M. Keiko; K. Yoshihiro. 2007. Emergence of Influenza B Viruses With Reduced Sensitivity to Neuraminidase Inhibitors. JAMA. 297:1435-1442.
  • 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 MD, Thanh, TT, Khanh, TH, Hien, VM, Smith, GJD, Chau, NV, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med 2005;353(25):2667-2672. PMID 16371632 (full text)
  • Hill G, Cihlar T, Oo C, Ho ES, 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.
  • Pediatric Advisory Committee. Pediatric safety update for Tamiflu. Rockville (MD): U.S. Food and Drug Administration; 2005.
  • 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)
  • Roche Laboratories, Inc. Tamiflu product information. Last updated Dec. 2005. (Accessed on 20 February, 2006 at http://www.rocheusa.com/products/tamiflu/pi.pdf) – prescribing information document from Roche
  • Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
  • 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)
  • Wong, Samson S.Y. and Yuen, Kwok-yung. Avian influenza virus infections in humans. Chest 2006; 129(1):156-168.
  • 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.
  • A Short Enantioselective Pathway for the Synthesis of the Anti-Influenza Neuramidase Inhibitor Oseltamivir from 1,3-Butadiene and Acrylic Acid Ying-Yeung Yeung, Sungwoo Hong, and E. J. Corey J. Am. Chem. Soc.; 2006; ASAP Web Release Date: 25-Apr-2006; (Communication) Abstract

For the Manfred Mann album, see 2006 (album). ... November 13 is the 317th day of the year (318th in leap years) in the Gregorian calendar, with 48 days remaining. ... For the Manfred Mann album, see 2006 (album). ... November 13 is the 317th day of the year (318th in leap years) in the Gregorian calendar, with 48 days remaining. ... The Australian Medicines Handbook or AMH is a medical reference text commonly used in practice by health professionals (particularly general practitioners and pharmacists) in Australia. ... The Journal of Organic Chemistry (abbreviated as ) is a scientific journal for original contributions of fundamental research in organic and bioorganic chemistry. ... The Journal of Organic Chemistry (abbreviated as ) is a scientific journal for original contributions of fundamental research in organic and bioorganic chemistry. ... Elias James Corey (born July 12, 1928) is an American organic chemist. ... The Journal of the American Chemical Society (usually abbreviated as , or JACS), is a peer-reviewed scientific journal, published since 1879 by the American Chemical Society. ...

See also

Amantadine, 1-aminoadamantane, is an antiviral drug that was approved by the FDA in 1976 for the treatment of influenza type A in adults. ... Rimantadine (systematic name 1-(1-aminoethyl)adamantane) is an orally administered medicine used to treat, and in rare cases prevent, Influenzavirus A infection. ... The M2 protein is a proton-selective ion channel protein, integral in the cell membrane of the influenza A virus. ... Avian influenza (also known as bird flu, avian flu, influenzavirus A flu, type A flu, or genus A flu) is a flu (influenza) due to a type of influenza virus that is hosted by birds, but may infect several species of mammals. ... Influenza A virus subtype H5N1, also known as A(H5N1) or simply H5N1, is a subtype of the Influenza A virus which can cause illness in humans and many other animal species. ... Influenza, commonly known as flu, is an infectious disease of birds and mammals caused by an RNA virus of the family Orthomyxoviridae (the influenza viruses). ... Zanamivir is a neuraminidase inhibitor used in the treatment of and prophylaxis of both influenza A and influenza B. Zanamivir was the first neuraminidase inhibitor commercially developed. ... Neuraminidase inhibitors are a class of antiviral drugs, whose mode of action relies on blocking the function of viral neuraminidase protein, thus preventing the virus from budding from the host cell. ...

External links

Wikimedia Commons has media related to:
  • 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).
  • www.tamiflu.com – Roche's page on Tamiflu (oseltamivir)
  • MedlinePlus Drug Information: oseltamivir (systemic) – information from USP DI Advice for the Patient
  • Pharmasquare – Tamiflu Mode of ActionFlash 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
  • Journal Response – Oseltamivir – abstracts of recent oseltamivir research

  Results from FactBites:
 
Oseltamivir - Wikipedia, the free encyclopedia (3104 words)
Oseltamivir is indicated for the treatment of infections due to influenza A and B virus in people at least one year of age, and prevention of influenza in people at least 1 year or older.
Oseltamivir was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005.
Oseltamivir 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.
Tamiflu Online, Description, Chemistry, Ingredients - Oseltamivir Phosphate - RxList Monographs (669 words)
Oseltamivir is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active form, oseltamivir carboxylate.
The proposed mechanism of action of oseltamivir is inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release.
The antiviral activity of oseltamivir carboxylate against laboratory strains and clinical isolates of influenza virus was determined in cell culture assays.
  More results at FactBites »

 
 

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