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Oseltamivir (Tamiflu) - First Oral Influenza Neuraminidase Inhibitor

Author: wikipedia, Posted on Sunday, November 20 @ 00:18:05 IST by RxPG  

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Pharmacology

Oseltamivir is an antiviral drug, a neuraminidase inhibitor used in the treatment and prophylaxis of both influenza A and influenza B. Oseltamivir was the first orally active neuraminidase inhibitor commercially developed*. It was developed by Gilead Sciences and is currently marketed by Swiss Company Roche under the trade name Tamiflu.

Mechanism of Action
Oseltamivir is a prodrug* (usually administered as phosphate), it is hydrolysed hepatically to the active metabolite, the free carboxylate of oseltamivir (GS4071). Like zanamivir, oseltamivir acts as a transition-state analogue inhibitor of influenza neuraminidase.

Side-Effects
In the clinical trials performed by Roche (comparing roughly 2,700 individuals given Tamiflu with 2,650 given placebo), nausea and vomiting were the most frequent adverse reactions reported.
General: Rash, swelling of face or tongue, toxic epidermal necrolysis
Digestive: Hepatitis, liver function tests abnormal
Cardiac: Arrhythmia
Neurologic: Seizure, confusion
Metabolic: Aggravation of diabetes
In May 2004, the safety division of Japan's health ministry ordered changes to the literature accompanying oseltamivir to add neurological and psychological disorders as possible side effects, including: impaired consciousness, abnormal behavior, and hallucinations. According to Japan's Pharmaceuticals and Medical Devices Agency there were 64 cases of psychological disorders linked to the drug between fiscal years 2000 and 2004.

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In February 2004, a 17-year-old male jumped in front of a truck and died after taking one capsule of Tamiflu. In February 2005, a 14-year-old male died after falling nine stories from his condominium building. A third teen reportedly attempted to jump from the window of a building. The two deaths were reported to the Japanese health ministry by Chugai Pharmaceutical Co., a corporation half-owned by Roche which distributes Tamiflu in Japan (Japan Times November 13, 2005; Reuters Nov 14, 2005).
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Another adverse reaction added to the Japanese list was haemorrhagic Colitis.

Oseltamivir, otherwise known as Tamiflu, 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, United States and Australia stockpiled quantities of oseltamivir in preparation for a possible pandemic. Though significant, the quantities stockpiled would not have been sufficient to protect the entire population of these countries.

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

However, 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. 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. The shikimic acid is extracted from the seeds in a ten-stage manufacturing process. 13 grams of star anise makes 1.3 grams of shikimic acid, which can be made into 10 Tamiflu capsules. 90% of the harvest is already used by Roche in making Tamiflu.
Some academic experts and other drug companies are disputing the difficulty of producing shikimic acid by means other than star anise extraction. An alternate method for production of the acid involves fermentation of genetically modified bacteria. Other potential sources of shikimic acid include the ginko tree. In addition, quinic acid, derived from the bark of the cinchona tree of Zaire, is a potential alternate base material for the production of oseltamivir.

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). 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. Secondly, Kiso et al. (2004) claim to have used more rigorous detection techniques than previous studies. Thirdly, the dosage regimen in Japan is different from other nations and some children may have been given a suboptimal dosage of oseltamivir. Partial resistance has also been detected in one girl suffering from the H5N1 avian influenza in Vietnam. She was being treated with oseltamivir at time of detection (Le et al, 2005; World Health Organization, 2005). 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 there are relatively few variations, and is also evidence that variations which do occur tend to be less "fit". Thus, mutations which 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 which 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 transmission.

Other actions
Tamiflu also appears to be active against
- canine parvovirus
- feline panleukopenia
- the canine respiratory complex known as "kennel cough"
- the emerging disease dubbed "canine flu," an equine virus that began affecting dogs in 2005.
Veterinary investigation of its use for canine parvo and canine flu is ongoing, but many shelters and rescue groups have reported great success employing Tamiflu in the early stages of these illnesses.


Note: This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Oseltamivir".



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