Oseltamivir

A scientist investigating avian influenza stated that he and his colleagues have personal stocks of Tamiflu. Some UT traditions include:. This argument lacks face validity, since treatment must begin before such tests results would be available anyway. Texas is a tradition-rich school, and many of those traditions are associated with athletics events, especially football. 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. In addition, the University of Texas has numerous practice, training, and intramural facilities. [22][23]. Major sporting facilities and their main use include:.

However, sophisticated criminals could produce convincing fake packaging in the future. Texas is also the biggest rival of the University of Arkansas which perhaps may be attributed to their long tenure as the two eponymous state schools of the former Southwest Conference, or to the 1969 game between the two, which decided the national championship in favor of the Longhorns. 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. This list includes most other colleges in Texas, but especially Baylor (located just up Interstate 35 from UT), Texas Tech, and Houston. The packages were labeled Generic Tamiflu. Perhaps due to the Longhorns' enduring athletic success, many other schools consider UT among their biggest rivals. In December 2005, 53 packages of fake Tamiflu pills were intercepted by the US Customs Service in South San Francisco. Aspects of the rivalry include:.

This is genuinely a potential problem, but, in the face of a shortage, some individuals may be willing to face such a risk. The football game between University of Texas and Oklahoma is known as the "Red River Shootout" (the official name of the event was changed to "Red River Rivalry", most likely due to political correctness) and is held annually in Dallas, Texas at the Cotton Bowl. Another argument is that it would be difficult for home users to determine whether illegally-imported Tamiflu is counterfeit. In recent years, this rivalry has taken on added significance, since both football programs have been highly ranked and compete in the same division of the Big 12 conference. 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). There is also a long-standing rivalry with the University of Oklahoma. 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. Aspects of the rivalry include:.

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. At the end of the year, the school with the most points wins the series and will receive a trophy. 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. Essentially, each time the two schools meet in a sport, the winner of the matchup gets a point. Several American states, including Massachusetts and Colorado, have issued advisories strongly discouraging this practice. In an attempt to generate more attention for the rivalry in sports other than football, in 2004 the two schools started the Lone Star Showdown, a trial two-year program. The short supply of Tamiflu has prompted some individuals to stockpile the drug. The annual football game with Texas A&M takes place the day after Thanksgiving each year.

On the other hand, at least one Democratic Senator has criticized Bush for not planning to buy enough anti-viral drugs [21]. The Texas/Texas A&M rivalry has given rise to several stereotypes on both sides: Aggies are generally portrayed as ignorant and dumb farmers, while Longhorns are portrayed as highbrow and arrogant city-slickers. Previously, Rumsfeld has been implicated in a racketeering lawsuit involving the FDA approval of the artificial sweetner aspartame [20]. Texas has other important rivalries as well. The rise in Gilead's share prices from $35 to $57 per share will have added between $2.5 million to $15.5 million to Rumsfeld's net worth. The University's biggest rival is Texas A&M University, although UT considers the Oklahoma Sooners to also be important rivals in football, especially in recent years due to the prominence of both programs. 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 women's volleyball club won National Championship honors at the National Intramural-Recreational Sports Association Collegiate Volleyball Sport Club Championships April 14 - April 16, 2005 in Kansas City, Missouri.

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. Some of these teams compete with other university clubs. Some commentators (e.g., [18]) question the motives of the U.S. UT offers a large number of intramural sports opportunities. Bush's plan included $1.4 billion for government purchases of anti-viral drugs[17]. The table at right shows Longhorn medals won in the Summer Olympics. 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]. Several Longhorn athletes have had success at the Olympics over the years.

president George W. Volleyball achieved titles in 1981 and 1988. In November, 2005, U.S. Women's track and field achieved national indoor titles in 1986, 1988, 1990, 1998-99, and outdoor titles in 1982, 1986, 1998-99, 2005. The week before, Thai authorities said they would begin producing oseltamivir by February 2006, claiming that Roche had not patented Tamiflu in Thailand[15]. Women's tennis claimed the title in 1993 and 1995. On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir[14]. Texas women's cross country won a National Title in 1986.

Roche said it would instead send all supplies to China's health ministry[13]. In addition, Texas has won nine National Titles in men's swimming and diving (1981, 1988-1991, 1996, 2000-2002) and nine in Women's Swimming and Diving (1981-82, 1984-88, 1990-91). [10][11][12] Sales were suspended in Hong Kong as well, and on November 8, also in China. Two longstanding traditions exist in which the fans interact with the team and each other; when Texas makes a stuff block, the players yell "Whose House?" and the fans respond with "Horns' House!" In addition, whenever a point is made by Texas, the announcer will say "Point Texas!" and the fans respond with "Point Texas!". 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. The team plays home games in Gregory Gymnasium. 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 also sent Demetria Sance to the 2000 Summer Olympics in Atlanta, Georgia.

Also in October, it was announced that Roche was in discussions with four generic drug manufacturers about possibly issuing sublicenses to increase production. Texas won the national championship in 1981 and 1988 and was runner-up to Nebraska in 1995. Cipla argues that it can legally sell oseltamivir to India and 49 other less-developed countries, possibly as early as January 2006. Texas has a strong women's volleyball tradition, with its teams finishing in the top 25 in the nation 19 out of the last 23 years, as well as two #2 finishes. 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. The women's gymnastics team won a national title on April 16, 2005 at the Association of Intercollegiate Gymnastics Clubs competition, and the men's team finished second, missing out on the national title by seven-tenths of a point to Penn State. In October 2005, the Indian drug company Cipla announced their plan to begin manufacture of generic oseltamivir without license from Roche. However, the University is home to two club gymnastics teams.

Though significant, the quantities stockpiled would not have been sufficient to protect the entire population of these countries. The University of Texas does not field a varsity gymnastics squad. 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. Legendary golf instructor Harvey Penick was a long-time Texas coach. Oseltamivir, otherwise known as Tamiflu, was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. Several former Longhorn players have gone on to success on the PGA Tour including: Tom Kite, Ben Crenshaw, Phil Blackmar, Mark Brooks, Bob Estes, and Justin Leonard. 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. Texas has a strong golf tradition, winning National Titles in 1971 and 1972 and finishing runner-up four other times.

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. The team plays home games on Disch-Falk Field. 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. In January of 2006, Texas is listed at number 1 in both major pre-season polls. Other potential sources of shikimic acid include the ginko tree. Former Longhorns who went on to success in the pros include Roger Clemens, Calvin Schiraldi, Burt Hooton, Keith Moreland, Spike Owen, Greg Swindell, and many more. An alternative method for production of the acid involves fermentation of genetically-modified bacteria. The team was runner-up 5 other times: 1953, 1984, 1985, 1989, and 2004.

Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid by means other than star anise extraction. Texas has won the College World Series 6 times: 1949, 1950, 1970, 1983, 2002 and 2005. The northern Vietnamese province of Lang Son has 80 km² of star anise.[7]. Texas has also won more individual games in the CWS than any other school, though they do not have the most championships. Ninety percent of the harvest is already used by Roche in making Tamiflu. The University's baseball team is considered one of the best in the nation with more trips to the College World Series than any other school, extending their record in 2005 to 32 appearances. Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 Tamiflu capsules. As of January 15th, Texas is 13-2 and ranked eighth after beating third-ranked Villanova.

The shikimic acid is extracted from the seeds in a ten-stage manufacturing process. This year (2005-2006) they went into the season ranked #2 in the nation until they were beat by the #1 Duke Blue Devils in East Rutherford, New Jersey and the Tennessee Volunteers. Star anise is grown in four provinces in China and harvested between March and May. Both teams play home games in the Frank Erwin Special Events Center. A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as at 2005). The women's basketball team has long been a national power, especially during the late 1980s (winning a National Title in 1986) and through the 1990s. 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. In 2003, the basketball team advanced to the NCAA Tournament Final Four round, and in 2004 advanced to the Sweet Sixteen round.

(See Pandemic Fears, below). In recent years, the men's basketball team has gained prominence. In early-2005, Roche announced a production shortage. * Rankings are from the Associated Press poll released prior to each game.
† First national championship since 1970 (BCS, AP). (2004) all appeared within individual children after treatment with oseltamivir - the children did not catch the resistant strains in human-to-human transmission. Texas and USC ended up winning out their seasons and faced each other in the National Championship, which Texas won 41-38. It is worth noting that the oseltamivir-resistant strains detected by Kiso et al. However, USC remained atop both human polls and was able to reclaim the top overall ranking.

Second, the development of a robust, resistant virus strain appears to be less likely (Ward et al., 2005). With the October 31st BCS rankings, Texas remained first in the computer rankings, with Virginia Tech actually pulling even with USC for number 2 in the computer rankings. First, these drugs work on a broader spectrum of influenza strains. The stay at the top was short-lived. The lack of variation in neuraminidase gives two advantages to oseltamivir and zanamivir, the drugs that target that enzyme. ^[3] The 0.0007 percent margin separating Texas from USC was the slimmest margin between the top two teams since the inception of BCS rankings.^[4]. 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 first place ranking was the first ever for UT in the BCS era, and the first top ranking in any major football poll since October 8th, 1984, when they were atop both the Associated Press and Coaches polls.

The genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. On October 24, Texas passed USC in the Bowl Championship Series rankings due to a strong showing in the computer rankings, which favored the Longhorns because of the overall strength of their opponents as well as the previous week's win over previously unbeaten Texas Tech. Kiso et al. (2004) suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic. They maintained those rankings throughout the entire 2005 - 2006 season. 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. Texas was given a pre-season #2 ranking (behind defending National Champions University of Southern California) by Sports Illustrated magazine, and was also ranked second in the AP and USA Today coaches pre-season polls. 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. With the exception of Cedric Benson, Derrick Johnson, and Bo Scaife, Texas returned most of their key players from 2004 - 2005, including red-shirt Junior Quarterback Vince Young.

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. Brown, who was often lauded for his recruiting while being criticized for failing to win championships, followed up a strong 2004 season on the field with an extremely successful 2005 recruiting season by securing the top-ranked recruiting class (the 2005 recruiting season is for players entering the University in Fall 2006). They suggest that the emergence of a resistant strain may be associated with a patient's clinical deterioration. The Longhorns are currently coached by Mack Brown and led on the field by quarterback Vince Young. (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. Three ex-Longhorns from the 2005 Rose Bowl team, Cedric Benson, Derrick Johnson, and Bo Scaife, were selected in the 2005 NFL Draft. de Jong et al. The Longhorns defeated the Wolverines 38-37 thanks to a successful field goal kick by Dusty Mangum as time expired off the clock.

She was being treated with oseltamivir at time of detection (Le et al., 2005; World Health Organization, 2005). The game was the first meeting between the two storied teams and the Longhorns' first trip to the Rose Bowl for a BCS game. High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. Under the current bowl system, the Longhorns played their first Bowl Championship Series game in 2005 at the Rose Bowl against the University of Michigan. 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. The improvements are scheduled to be completed before the 2006-2007 football season.^[2]. Second, Kiso et al. (2004) claim to have used more rigorous detection techniques than previous studies. The stadium is undergoing renovations scheduled to start November 14, 2005, two days following UT's last home football game of the season.

First, children typically have a longer infection period, giving a longer time for resistance to develop. Royal-Texas Memorial Stadium which has a seating capacity of 80,082. Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. The team currently plays home games in Darrell K. 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). During the late 1980s and 1990s, the team was somewhat less successful, but has recently returned to prominence, finishing in the top ten in 2001, 2002, 2004, and 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). Only two programs, Notre Dame and the University of Michigan, have won more games than Texas.

Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme (Ward et al., 2005). The Longhorns have a long tradition of winning football games. The resistance rate reported during clinical trials up to July 2004 was 0.33% in adults, 4.0% in children, and 1.26% overall. Other former Longhorn greats include: Scott Appleton, Tommy Nobis, Bobby Layne, Tom Landry, Jerry Sisemore, Brad Shearer, Kenneth Sims, Tony Degrate, Doug English, Jerry Gray, Eric Metcalf, Tony Brackens, Priest Holmes, and many more. 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. Two Texas Longhorn running backs have won college football's highest honor, the Heisman Trophy: Earl Campbell (1977) and Ricky Williams (1998). Roche has other routes to Tamiflu that do not involve the use of (−)-shikimic acid as a chiral pool starting material, such as a Diels-Alder route involving furan and ethyl acrylate or an isophthalic acid route, which involves catalytic hydrogenation and enzymatic desymmetrization. The team experienced its greatest success when it was coached by Darrell Royal, under Royal winning three National Championships — 1963, 1969 and 1970.

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. From 1936 to 2004, the team finished the season in the top ten 23 times, or one-third of the time, according to the Associated Press. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. The University of Texas has traditionally been considered a college football powerhouse, with four national titles to their credit, including the 2005-2006 season. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. The mascot is a Texas longhorn named Bevo. Selective acylation with acetic anhydride (under buffered conditions, the 5-amino group is protonated owing to a considerable difference in pK_a, 4.2 vs 7.9, preventing acetylation) yields the desired N-acetylated product in crystalline form upon extractive workup. The school's colors are burnt orange and white, and its alma mater is The Eyes of Texas.^[1] At football games, students frequently sing Texas Fight, the University's fight song.

Acidic hydrolysis then removed the imine. A charter member of the Southwest Conference until its dissolution in 1996, Texas now competes in the Big 12 Conference (South Division) of the NCAA's Division I-A. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. . Mesylation, followed by removal of the solid byproduct triethylamine hydrochloride, results in an intermediate that was poised to undergo aziridination upon transimination with another equivalent of allylamine. Due to the breadth of sports offered and the quality of the programs, Texas was selected as "America's Best Sports College" in a 2002 analysis performed by Sports Illustrated. 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. The University of Texas offers a wide variety of varsity and intramural sports programs.

Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. The women's teams are sometimes called the Lady Longhorns, but generally both the men's and women's teams are referred to as the Longhorns. 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 University of Texas at Austin (often referred to as simply the University of Texas, Texas, or the abbreviation UT) is the flagship institution of the University of Texas System. 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. These teams are referred to as the Texas Longhorns, taking their name from the Longhorn cattle that were an important part of the development of Texas. The corresponding epoxide is formed under basic conditions with potassium bicarbonate. Texas Longhorn Athletics programs include the extramural and intramural sports teams of The University of Texas.

Reductive opening of the ketal under modified Hunter conditions (JOC 1993, 58, 6756) in dichloromethane yields an inseparable mixture of isomeric mesylates. 1 in BCS ahead of USC October 25, 2005 The San Diego Union-Tribune. 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. ^  Harmonson, Todd Texas ascends to No. The synthesis commences from naturally available (−)-shikimic acid. ^  Veyhl, Jake Longhorns Number 1 for First Time in BCS Rankings October 25, 2005 The Daily Texan. The reported azide-free Roche synthesis of tamiflu is summarized graphically below:. ^  Young, Meghan Regents approve stadium upgrades November 10, 2005 The Daily Texan.

However, it is known that one adverse reaction added to the Japanese list was haemorrhagic Colitis (bloody diarrhoea)[6].. "Eyes of Texas" Handbook of Texas Online. The authors of this section have yet to find Japan's actual listing of adverse reactions linked to oseltamivir. ^  Berry, Margaret C. They did recommend adding a warning to prescription information regarding possible rashes. Texas coach Darrell Royal replied, "We're ready." and the Longhorns went on to win the game. 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). At the time, the prevailing custom was for the final polls to come out in advance of the bowl game, meaning Texas had already been crowned the National Champions.