WinMX

When WinMX tries to find the FrontCode peer caches (central servers essential for the operation of WinMX), it is instead directed to look up one of the new peer caches set up by the WinMX community. A scientist investigating avian influenza stated that he and his colleagues have personal stocks of Tamiflu. These patches work by modifying the DNS lookup WinMX uses to find peer caches. This argument lacks face validity, since treatment must begin before such tests results would be available anyway. By September 25, 2005, users were able to download a working software patch for WinMX from two websites known as WinMX Group [2] and Vladd44 [3]. 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. It is suggested for WinMX users to either apply a patch which would connect them to a user-driven WinMX network, or move on to a decentralized file sharing network such as Gnutella or the eDonkey network. [22][23].

Under the threat of litigation, on September 21, 2005 the network and the WinMX homepage were confirmed offline. However, sophisticated criminals could produce convincing fake packaging in the future. On September 13, 2005, Frontcode Technologies received a cease and desist letter from the RIAA asking them to implement filters to make it impossible for users to download copyrighted material from WinMX, or shut down. 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. During March 2005, The NPD Group found that WinMX was used in more US households than any other P2P client or legal music downloading service [1], although this claim is disputed. The packages were labeled Generic Tamiflu. As a result, it took additional effort to find the available downloads from within the list, although with practice, this was easily done. In December 2005, 53 packages of fake Tamiflu pills were intercepted by the US Customs Service in South San Francisco.

In many cases, one could see a desired file, but could not download it since most of the listed selections were inaccessible. This is genuinely a potential problem, but, in the face of a shortage, some individuals may be willing to face such a risk. One of the major problems that led to the declining popularity of WinMX was the increase presence of "dummy" files, reportedly placed by individuals and/or companies opposed to file sharing. Another argument is that it would be difficult for home users to determine whether illegally-imported Tamiflu is counterfeit. This turned out to be untrue. 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). In early 2004, rumors circulated in Hong Kong that the Hong Kong Customs Department was prosecuting people using WinMX to share copyrighted items. 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.

WinMX is also especially popular in Italy and Hong Kong. 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. However, WinMX's Japanese popularity dropped sharply with the arrest of several users, and resulted in the development of a semi-secure, encrypted, serverless application called WinNY (N comes after M, Y comes after X). 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. By 2001 it was the de facto P2P application in Japan. Several American states, including Massachusetts and Colorado, have issued advisories strongly discouraging this practice. WinMX was very popular in Japan due to its ability to handle 2 byte characters. The short supply of Tamiflu has prompted some individuals to stockpile the drug.

The client application Lopster used to have WPNP 2 support, although it was locked out with the arrival of WPNP 3. On the other hand, at least one Democratic Senator has criticized Bush for not planning to buy enough anti-viral drugs [21]. Some consider WinMX a much safer downloading program than Kazaa, partly due to the fact that no spyware and adware comes with WinMX. Previously, Rumsfeld has been implicated in a racketeering lawsuit involving the FDA approval of the artificial sweetner aspartame [20]. Downloads can be very fast for popular songs since the user can run a "multi-point download" that simultaneously downloads the same file in small pieces from several users. 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. Frontcode had operated several cache servers to aid WPNP network operation. 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]).

WPNP version 2 was phased out as WinMX 3.0 and its WPNP version 3 protocol came into existence. 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. WinMX began its life as an OpenNAP client capable of connecting to several servers simultaneously, although Frontcode later created a proprietary protocol, termed WinMX Peer Network Protocol (WPNP), which was used starting with WinMX 2 in May 2001. Some commentators (e.g., [18]) question the motives of the U.S. The official WinMX website and WinMX servers have been offline since September 2005 due to a lawsuit (see the "Decline" section below), though the application remains operable through third-party modifications. Bush's plan included $1.4 billion for government purchases of anti-viral drugs[17]. WinMX is a peer-to-peer file sharing program authored by Frontcode Technologies and running on Windows operating systems. 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].

president George W. In November, 2005, U.S. The week before, Thai authorities said they would begin producing oseltamivir by February 2006, claiming that Roche had not patented Tamiflu in Thailand[15]. On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir[14].

Roche said it would instead send all supplies to China's health ministry[13]. [10][11][12] Sales were suspended in Hong Kong as well, and on November 8, also in China. 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. 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.

Also in October, it was announced that Roche was in discussions with four generic drug manufacturers about possibly issuing sublicenses to increase production. Cipla argues that it can legally sell oseltamivir to India and 49 other less-developed countries, possibly as early as January 2006. 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. In October 2005, the Indian drug company Cipla announced their plan to begin manufacture of generic oseltamivir without license from Roche.

Though significant, the quantities stockpiled would not have been sufficient to protect the entire population of these countries. 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. Oseltamivir, otherwise known as Tamiflu, was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. Veterinary investigation of its use for canine parvo [8] and canine flu [9]is ongoing, but many shelters and rescue groups have reported great success employing Tamiflu in the early stages of these illnesses.

Tamiflu appears to be active against canine parvovirus, feline panleukopenia, the canine respiratory complex known as "kennel cough," and the emerging disease dubbed "canine flu", an equine virus that began affecting dogs in 2005. In addition, quinic acid, derived from the bark of the cinchona tree of Zaire, is a potential alternative base material for the production of oseltamivir. Other potential sources of shikimic acid include the ginko tree. An alternative method for production of the acid involves fermentation of genetically-modified bacteria.

Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid by means other than star anise extraction. The northern Vietnamese province of Lang Son has 80 km² of star anise.[7]. Ninety percent of the harvest is already used by Roche in making Tamiflu. Thirteen grams of star anise make 1.3 grams of shikimic acid, which can be made into 10 Tamiflu capsules.

The shikimic acid is extracted from the seeds in a ten-stage manufacturing process. Star anise is grown in four provinces in China and harvested between March and May. A shortage of star anise is one of the key reasons why there is a worldwide shortage of Tamiflu (as at 2005). 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.

(See Pandemic Fears, below). In early-2005, Roche announced a production shortage. (2004) all appeared within individual children after treatment with oseltamivir - the children did not catch the resistant strains in human-to-human transmission. It is worth noting that the oseltamivir-resistant strains detected by Kiso et al.

Second, the development of a robust, resistant virus strain appears to be less likely (Ward et al., 2005). First, these drugs work on a broader spectrum of influenza strains. The lack of variation in neuraminidase gives two advantages to oseltamivir and zanamivir, the drugs that target that enzyme. 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 genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. Kiso et al. (2004) suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic. 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. 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.

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. They suggest that the emergence of a resistant strain may be associated with a patient's clinical deterioration. (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. de Jong et al.

She was being treated with oseltamivir at time of detection (Le et al., 2005; World Health Organization, 2005). High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. 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. Second, Kiso et al. (2004) claim to have used more rigorous detection techniques than previous studies.

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

Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme (Ward et al., 2005). The resistance rate reported during clinical trials up to July 2004 was 0.33% in adults, 4.0% in children, and 1.26% overall. As with other antivirals, resistance to the agent was expected with widespread use of oseltamivir, though the emergence of resistant viruses was expected to be less frequent than with amantadine or rimantadine. Roche has other routes to Tamiflu that do not involve the use of (−)-shikimic acid as a chiral pool starting material, such as a Diels-Alder route involving furan and ethyl acrylate or an isophthalic acid route, which involves catalytic hydrogenation and enzymatic desymmetrization.

It is noted that the synthesis avoids the use of potentially explosive azide reagents and intermediates; however, the synthesis actually used by Roche uses azides. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. Selective acylation with acetic anhydride (under buffered conditions, the 5-amino group is protonated owing to a considerable difference in pK_a, 4.2 vs 7.9, preventing acetylation) yields the desired N-acetylated product in crystalline form upon extractive workup.

Acidic hydrolysis then removed the imine. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. Mesylation, followed by removal of the solid byproduct triethylamine hydrochloride, results in an intermediate that was poised to undergo aziridination upon transimination with another equivalent of allylamine. The aminoalcohol was converted directly to the corresponding allyl-diamine in an interesting cascade sequence that commences with the unselective imination of benzaldehyde with azeotropic water removal in methyl tert-butyl ether.

Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. The water-immiscible solvents methyl tert-butyl ether and acetonitrile are used to simplify the workup procedure, which involved stirring with 1 M aqueous ammonium sulfate. Using the inexpensive Lewis acid magnesium bromide diethyl etherate (commonly prepared fresh by the addition of magnesium turnings to 1,2-dibromoethane in benzene:diethyl ether), the epoxide is opened with allyl amine to yield the corresponding 1,2-amino alcohol. The corresponding epoxide is formed under basic conditions with potassium bicarbonate.

Reductive opening of the ketal under modified Hunter conditions (JOC 1993, 58, 6756) in dichloromethane yields an inseparable mixture of isomeric mesylates. The 3,4-pentylidene acetal mesylate is prepared in three steps: esterification with ethanol and thionyl chloride; ketalization with para-toluenesulfonic acid and 3-pentanone; and mesylation with triethylamine and methanesulfonyl chloride. The synthesis commences from naturally available (−)-shikimic acid. The reported azide-free Roche synthesis of tamiflu is summarized graphically below:.

However, it is known that one adverse reaction added to the Japanese list was haemorrhagic Colitis (bloody diarrhoea)[6].. The authors of this section have yet to find Japan's actual listing of adverse reactions linked to oseltamivir. They did recommend adding a warning to prescription information regarding possible rashes. The Committee stated that there was insufficient evidence to claim a causal link between oseltamivir use and the deaths of 12 Japanese children (only two from neurological problems).

Chem. 2001, 66, 2044-2051. Org. J. Synthesis of Tamiflu.

Chem. 1998, 63, 4545-4550. Org. J. (Accessed October 12, 2005, at http://www.who.int/csr/resources/publications/influenza/WHO_CDS_CSR_GIP_2005_7/en/.).