Oseltamivir

 
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What is/are Oseltamivir?

Oseltamivir INN /ɒsəlˈtæmɨvɪər/, marketed under the trade name Tamiflu, is an antiviral drug, which may slow the spread of influenza (flu) virus between cells in the body by stopping the virus from chemically cutting ties with its host cell. The drug is taken orally in capsules or as a suspension. It is used to treat influenza A virus and influenza B virus. Oseltamivir is a prodrug, a (relatively) inactive chemical, which is converted into its active form by metabolic process after it is taken into the body. It was the first orally active neuraminidase inhibitor commercially developed.[citation needed] It was developed by C.U. Kim, W. Lew, and X. Chen of US-based Gilead Sciences, and is marketed by Genentech.

Oseltamivir's effectiveness is debated among researchers, because its manufacturer, (Roche), originally refused to release the trial data for independent analysis. Analyses of published studies have concluded that neuramidase inhibitors such as oseltamivir may be modestly effective in decreasing the time people are sick and prevention of influenza A and B infections in children. However, this may be due to publication bias (publishing favorable studies and not publishing unfavorable studies), and it will not be possible to know until a review based on all of Roche's data is done, scheduled for the end of 2013. Together these published studies suggest oseltamivir reduces the median time to symptom alleviation 0.5–1 day. It is unclear if this medication affects transmission of influenza in adults. They however can increase rates of vomiting.

As of December 15, 2010, the World Health Organization (WHO) reported 314 samples of the prevalent 2009 pandemic H1N1 flu tested worldwide have shown resistance to oseltamivir.[10] However, The predominant strains of both influenza A and influenza B active during the 2012-2013 flu season in the US are sensitive to oseltamivir.

Medical uses

Oseltamivir is indicated for the treatment and prevention of infections due to influenza A and B viruses.] The Centers for Disease Control and Prevention recommends physicians prioritize which patients to whom they prescribe oseltamivir: specifically, people hospitalized with more severe illness, children younger than two years old, adults over 65, pregnant women, people with certain chronic medical or immunosuppressive conditions and adults under 19 on long-term aspirin therapy. However, they also advise children and adults presenting with suspected flu who have symptoms of lower respiratory tract illness or clinical deterioration should also receive prompt empiric antiviral therapy, regardless of previous health or age. The predominant strains of both influenza A and influenza B active during the 2012-2013 flu season in the US are sensitive to oseltamivir.

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. Accordingly, higher doses and longer durations of therapy have been suggested for treatment of patients with the H5N1 virus.

Clinical trials for an increased dosage began in May 2007. All avian influenza cases in Indonesia, Thailand, and Vietnam were inducted into the trial. The trial also included 100 cases of severe seasonal influenza from each of those countries and the United States. Half received the current standard dose, and half received a double dose, but for the standard length of time.

Efficacy

The efficacy of Oseltamivir is disputed, as a significant amount of its clinical trial data remains unpublished by the drug's manufacturers. A meta-analysis done by Kaiser et al. and supported by manufacturer Hoffmann-La Roche, was published in 2003. It concluded that oseltamivir can prevent complications of influenza such as pneumonia if it is taken within 48 hours of the first appearance of influenza symptoms. Kaiser's study was based on a summary of ten randomised controlled trials, of which only two had been published.

The Cochrane Collaboration had originally supported conclusions by Kaiser that the antiviral drug can ward off pneumonia and other serious conditions linked to influenza, but in 2009 reversed its previous findings. A previously published version of their review had included all trials mentioned in Kaiser's 2003 meta-analysis, even the unpublished ones. In 2009 they decided to exclude the unpublished trials. The Cochrane review reported an analysis of 20 studies which showed oseltamivir offered mild benefits in terms of duration of symptoms for healthy adults if taken within 24 hours of onset of symptoms, but found no clear evidence it prevented lower respiratory tract infections or other complications of influenza.These findings relate only to its use in healthy adults with influenza, not in patients judged to be at high risk of complications. It may still be a useful drug for reducing the duration of symptoms, although for this use it still has yet to be compared with NSAIDs or paracetamol.

Roche commissioned an independent reanalysis of its data in 2011. One of the authors had received income from an organization sponsored by Roche previous but they were not funded by Roche for this analysis. They concluded that early oseltamivir use reduced the number of lower respiratory tract infection treated with antibiotics from 9.3% to 5.9% in hitherto healthy adults and children. No benefit occurred in those without an infection with influenza.

A subsequent Cochrane review, in 2012, maintains that significant parts of the clinical trials still remains unavailable for public scrutiny, and that the available evidence is not sufficient to conclude that oseltamivir decreases hospitalizations from influenza-like illnesses. As of October 2012, 60% of Roche's clinical data concerning oseltamivir remains unpublished.

Adverse effects

Common adverse drug reactions (ADRs) associated with oseltamivir therapy (occurring in over 1 percent of clinical trial participants) 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.

Various other ADRs have been reported in postmarketing surveillance, including: toxic epidermal necrolysis, cardiac arrhythmia, seizure, confusion, aggravation of diabetes, and haemorrhagic colitis. There are concerns that oseltamivir may cause dangerous psychological, neuropsychiatric side effects including self-harm in some users. These dangerous side effects occur more commonly in children than in adults. This stems from cases in Japan, where the drug is most heavily prescribed, consuming 60 percent of the world's production.

In March 2007, Japan's Health Ministry warned that oseltamivir should not be given to those aged 10 to 19. 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.

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 falls from buildings after taking oseltamivir, and one 17-year-old died after he jumped in front of a truck.[26] 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 from these actions.

In October 2006, Shumpei Yokota, a professor of pediatrics at Yokohama 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. Chugai Pharmaceutical Co. (which produces oseltamivir in Japan[citation needed]) gave Yokota's department 10 million yen (about US$105,000) over five years.

To determine whether to lift the 2007 ban, a research team from the Japanese Health, Labour and Welfare Ministry studied 10,000 children under the age of 18 who had been diagnosed with influenza since 2006. The study was finalized in April 2009. Taking into account all degrees of abnormal behavior, including minor behavioral problems such as incoherent speech, the study found children who took oseltamivir were 54 percent more likely to exhibit abnormal behaviour than those who did not take the drug. When the team limited its analysis to children who had displayed serious abnormal behavior that led to injury or death, it found those who had taken oseltamivir were 25 percent more likely to behave unusually.

In November 2006, the U.S. Food and Drug Administration (FDA) amended the warning label to include the possible side effects of delirium, hallucinations, or other related behavior.] 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). The change to a more cautionary stance was attributed to 103 new reports 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.

Roche points out[when?] that oseltamivir has been used to treat over 50 million people since 1999, and states the influenza may itself cause psychological problems. 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. In April 2007, South Korea issued a safety warning against prescribing oseltamivir to teenagers except in special cases.

A joint investigation by the British Medical Journal (BMJ) and British TV Channel 4 published in the BMJ on December 8, 2009, concluded that in otherwise healthy adults they "have no confidence in claims that oseltamivir reduces the risk of complications and hospital admission in people with influenza" and believe it should not be used in routine control of seasonal influenza. There was also concern about underreporting of side effects of the drug. In contrast, according to the BMJ, Roche has stated in media briefings that oseltamivir reduced hospital admissions by 61 percent; secondary complications (including bronchitis, pneumonia, and sinusitis) by 67 percent in otherwise healthy individuals and lower respiratory tract infections requiring antibiotics by 55 percent.

BMJ editor Dr. Fiona Godlee, said "claims that oseltamivir reduces complications have been a key justification for promoting the drug's widespread use. Governments around the world have spent billions of pounds on a drug that the scientific community has found itself unable to judge."
Mutagenesis

Although found to be nonmutagenic in the Ames test and the mouse micronucleus test, oseltamivir tested positive in the Syrian hamster embryo (SHE) cell transformation test.

Mechanism of action

The prodrug oseltamivir is itself not virally effective; however, once in the liver it is hydrolysed to its active metabolite - the free carboxylate of oseltamivir (GS4071). Oseltamivir is a neuraminidase inhibitor, serving as a competitive inhibitor of the activity of the viral neuraminidase (NA) enzyme upon sialic acid, found on glycoproteins on the surface of normal host cells. By blocking the activity of the enzyme, oseltamivir prevents new viral particles from being released by infected cells.

This article uses material from the Wikipedia article Oseltamivir, which is released under the Creative Commons Attribution-Share-Alike License 3.0.

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