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Tamiflu Protecion Against Influenza And Avian Flu
Tamiflu Protecion Against Influenza And Avian Flu (INN) (IPA: [ɒsɛlˈtæmɪvir]) is an antiviral drug used in the treatment and prophylaxis of both Influenzavirus A and Influenzavirus B. Like zanamivir, Tamiflu Protecion Against Influenza And Avian Flu is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells.
Tamiflu Protecion Against Influenza And Avian Flu 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 Tamiflu Protecion Against Influenza And Avian Flu (GS4071). It was developed by Gilead Sciences and is currently marketed by Hoffmann-La Roche (Roche) under the trade name Tamiflu.
With increasing fears about the potential for a new influenza pandemic, Tamiflu Protecion Against Influenza And Avian Flu has received substantial media attention. Production capacity is limited, and governments are stockpiling the drug.
Indications and dosage of Tamiflu Protecion Against Influenza And Avian Flu
Tamiflu Protecion Against Influenza And Avian Flu 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. 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. Tamiflu Protecion Against Influenza And Avian Flu 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 of Tamiflu in avian influenza
It has been suggested that higher doses and longer durations of therapy should be used for treatment of patients with H5N1-type influenza A virus infection (avian influenza). It has been found that the standard recommended dose incompletely suppresses viral replication in at least some patients with H5N1 influenza, rendering therapy ineffective and increasing the risk of viral resistance. (de Jong et al., 2005)
Co-administration with probenecid
It has been suggested that co-administration of Tamiflu Protecion Against Influenza And Avian Flu with probenecid could extend the limited supply of Tamiflu Protecion Against Influenza And Avian Flu. Probenecid reduces renal excretion of the active metabolite of Tamiflu Protecion Against Influenza And Avian Flu. One study showed that 500 mg of probenicid given every six hours doubled both the peak plasma concentration (C max) and the half-life of Tamiflu Protecion Against Influenza And Avian Flu, 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, and is still currently used to increase penicillin concentrations in serious infections.
Dosage forms of Tamiflu Protecion Against Influenza And Avian Flu
Tamiflu Protecion Against Influenza And Avian Flu is marketed by Roche under the trade name Tamiflu, as capsules (containing Tamiflu Protecion Against Influenza And Avian Flu phosphate 98.5 mg equivalent to Tamiflu Protecion Against Influenza And Avian Flu 75 mg) and as a powder for oral suspension (Tamiflu Protecion Against Influenza And Avian Flu phosphate equivalent to Tamiflu Protecion Against Influenza And Avian Flu 12 mg/mL).
Adverse effects of Tamiflu Protecion Against Influenza And Avian Flu
Common adverse drug reactions (ADRs) associated with Tamiflu Protecion Against Influenza And Avian Flu therapy include: nausea, vomiting, diarrhoea, abdominal pain, and headache. Rare ADRs include: hepatitis and elevated liver enzymes, rash, allergic reactions including anaphylaxis, and Stevens-Johnson syndrome. (Rossi, 2006)
Various other ADRs have been reported in postmarketing surveillance including: toxic epidermal necrolysis, cardiac arrhythmia, seizure, confusion, aggravation of diabetes, and haemorrhagic colitis.
Neurological effects of Tamiflu Protecion Against Influenza And Avian Flu
In May 2004, the safety division of Japan's health ministry ordered changes to the literature accompanying Tamiflu Protecion Against Influenza And Avian Flu to add neurological and psychological disorders as possible adverse effects, including: impaired consciousness, abnormal behavior, and hallucinations. Various cases of psychological disorders were associated with Tamiflu Protecion Against Influenza And Avian Flu therapy between 2000–2004, including several deaths.
On 2005-11-18 the United States Food and Drug Administration (FDA) issued a report regarding the paediatric safety of Tamiflu Protecion Against Influenza And Avian Flu, which stated that there was insufficient evidence to claim a causal link between Tamiflu Protecion Against Influenza And Avian Flu use and the deaths of 12 Japanese children (only two from neurological problems). However, it was recommended that a warning was added to the Product Information regarding rashes associated with Tamiflu Protecion Against Influenza And Avian Flu therapy (Pediatric Advisory Committee, 2005).
Mode of action of Tamiflu Protecion Against Influenza And Avian Flu
Tamiflu Protecion Against Influenza And Avian Flu is a neuraminidase inhibitor. By blocking the activity of the neuraminidase, Tamiflu Protecion Against Influenza And Avian Flu prevents new viral particles from being released by infected cells.
Resistance to Tamiflu Protecion Against Influenza And Avian Flu
As with other antivirals, resistance to the agent was expected with widespread use of Tamiflu Protecion Against Influenza And Avian Flu, though the emergence of resistant viruses was expected to be less frequent than with amantadine or rimantadine. The resistance rate reported during clinical trials up to July 2004 was 0.33% in adults, 4.0% in children, and 1.26% overall. Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme (Ward et al., 2005).
Mutant H3N2 influenza A virus isolates resistant to Tamiflu Protecion Against Influenza And Avian Flu were found in 18% of a group of 50 Japanese children treated with Tamiflu Protecion Against Influenza And Avian Flu (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 Tamiflu Protecion Against Influenza And Avian Flu.
High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. She was being treated with Tamiflu Protecion Against Influenza And Avian Flu 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 Tamiflu Protecion Against Influenza And Avian Flu does not always completely suppress viral replication, a situation that could favor the emergence of resistant strains. Moscona (2005) gives a good overview of the resistance issue, and says that personal stockpiles of Tamiflu could lead to under-dosage and thus the emergence of resistant strains of H5N1.
Resistance is of concern in the scenario of an influenza pandemic, since resistance is more likely to develop due to the potentially longer duration of infection by novel viruses. Kiso et al. (2004) suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic.
The genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. This means that there are relatively few variations, and there is also evidence that variations that do occur tend to be less "fit." Thus, mutations that convey resistance to Tamiflu Protecion Against Influenza And Avian Flu 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 Tamiflu Protecion Against Influenza And Avian Flu 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 Tamiflu Protecion Against Influenza And Avian Flu-resistant strains detected by Kiso et al. (2004) all appeared within individual children after treatment with Tamiflu Protecion Against Influenza And Avian Flu – the children did not catch the resistant strains in human-to-human or bird-to-human transmission.
The synthesis commences from naturally available (−)-shikimic acid. The 3,4-pentylidene acetal mesylate is prepared in three steps: esterification with ethanol and thionyl chloride; ketalization with para-toluenesulfonic acid and 3-pentanone; and mesylation with triethylamine and methanesulfonyl chloride. Reductive opening of the ketal under modified Hunter conditions (JOC 1993, 58, 6756) in dichloromethane yields an inseparable mixture of isomeric mesylates. The corresponding epoxide is formed under basic conditions with potassium bicarbonate. Using the inexpensive Lewis acid magnesium bromide diethyl etherate (commonly prepared fresh by the addition of magnesium turnings to 1,2-dibromoethane in benzene:diethyl ether), the epoxide is opened with allyl amine to yield the corresponding 1,2-amino alcohol. The water-immiscible solvents methyl tert-butyl ether and acetonitrile are used to simplify the workup procedure, which involved stirring with 1 M aqueous ammonium sulfate. Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. The aminoalcohol was converted directly to the corresponding allyl-diamine in an interesting cascade sequence that commences with the unselective imination of benzaldehyde with azeotropic water removal in methyl tert-butyl ether. Mesylation, followed by removal of the solid byproduct triethylamine hydrochloride, results in an intermediate that was poised to undergo aziridination upon transimination with another equivalent of allylamine. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. Acidic hydrolysis then removed the imine. Selective acylation with acetic anhydride (under buffered conditions, the 5-amino group is protonated owing to a considerable difference in pK a, 4.2 vs 7.9, preventing acetylation) yields the desired N-acetylated product in crystalline form upon extractive workup. Finally, deallylation as above, yielded the freebase of Tamiflu Protecion Against Influenza And Avian Flu, which was converted to the desired Tamiflu Protecion Against Influenza And Avian Flu phosphate by treatment with phosphoric acid. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. It is noted that the synthesis avoids the use of potentially explosive azide reagents and intermediates; however, the synthesis actually used by Roche uses azides. Roche has other routes to Tamiflu Protecion Against Influenza And Avian Flu 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.
Production shortage/shikimic acid
In early 2005, Roche announced a production shortage. (See Pandemic Fears, below). According to Roche, the major bottleneck in Tamiflu Protecion Against Influenza And Avian Flu 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 Tamiflu Protecion Against Influenza And Avian Flu 75 mg capsules. Ninety percent of the harvest is already used by Roche in making Tamiflu Protecion Against Influenza And Avian Flu.
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 ginkgo tree. 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 Tamiflu Protecion Against Influenza And Avian Flu.
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 Tamiflu Protecion Against Influenza And Avian Flu 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).
In March 2006, Roche announced that it was making utilizing the resources of 15 external contractors in 9 countries, allowing production to expand to "as much as 400 million doses annually by the end of this year" [1].
Bird Flu Pandemic fears
Tamiflu Protecion Against Influenza And Avian Flu 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 Tamiflu Protecion Against Influenza And Avian Flu in preparation for a possible pandemic. Though large, the quantities stockpiled would not have been sufficient to protect the entire population of these countries.
Personal stockpiling of Tamiflu Protecion Against Influenza And Avian Flu
The short supply of Tamiflu Protecion Against Influenza And Avian Flu has prompted some individuals to stockpile the drug. Several American states, including Massachusetts and Colorado, have issued advisories strongly discouraging this practice.
One argument against individual stockpiling is that limited drugs should be kept for more strategic or ethical deployment, that is, to hard-hit areas, to people in critical roles (e.g., healthcare and government workers), to people vulnerable to seasonal flu, or to people who actually have come down with avian influenza. Ethical arguments are sometimes made: Why should affluent people (or nations) have preferred access to antiviral medications? Illegal importation may divert the drug from poorer countries where the risk of avian influenza is actually higher.
In the New England Journal of Medicine, Moscona (2005) argues that the use of personal stockpiles of Tamiflu Protecion Against Influenza And Avian Flu 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 Tamiflu Protecion Against Influenza And Avian Flu), but this may be insufficient for the treatment of H5N1. (de Jong et al., 2005)
Another argument is that it would be difficult for home users to determine whether illegally-imported Tamiflu is counterfeit. This is genuinely a potential problem, but, in the face of a shortage, some individuals may be willing to face such a risk. In December 2005, 53 packages of 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. [15][16]
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.
Veterinary use of Tamiflu
Tamiflu Protecion Against Influenza And Avian Flu 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 [17] and canine flu [18]is ongoing, but many shelters and rescue groups have reported great success employing Tamiflu Protecion Against Influenza And Avian Flu in the early stages of these illnesses.
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