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Oseltamivir adalah sebuah obat antiviral, sebuah inhibitor neuraminidase yang digunakan dalam penanganan influenza A dan B, dan

banyak dikenal sebagai obat yang dianjurkan untuk menangani flu burung.

Oseltamivir Cegah Pneumonia

Oseltamivir pernah mencapai puncak kejayaan saat wabah flu burung dan flu babi menimpa berbagai negara. Temuan baru di Cina menunjukkan antiviral ini tidak hanya melindungi orang dewasa muda yg terinfeksi virus flu babi H1N1 tetapi juga mencegah pneumonia. Paska pandemi flu H1N1 di 2009, virus ternyata telah "kawin" dengan virus influenza musiman, sehingga orang dewasa muda dan anak-anak yg terkena flu akan lebih parah gejalanya. Pada lansia bahkan banyak yg meninggal. Dalam penelitian yg dipimpin oleh Hongjie Yu Weizhong Yang di Pusat Pencegahan dan Pengendalian Penyakit Cina, mereka menemukan bahwa setelah dipertimbangkan faktor seperti usia, jenis kelamin, vaksinasi flu dan pemberian antibiotik, pengobatan oseltamivir merupakan faktor protektif yg signifikan terhadap pneumonia. Penelitian ini melibatkan 1.291 pasien yg dikonfirmasi mengidap infeksi H1N1 ringan selama pandemi 2009. Rata-rata usia mereka adalah 20 tahun dan 76% dari mereka diobati dengan oseltamivir sejak hari ketiga dari onset gejala. Dari 920 pasien yg mendapatkan X-Ray dada, 12% menunjukkan tanda-tanda ketidaknormalan yg mengindikasikan pneumonia. Namun, tak seorangpun berakhir di perawatan intensif dan tidak pula membutuhkan ventilasi mekanis. Efek perlindungan ini terlihat pada semua pasien termasuk mereka yg memulai pengobatan lebih dari dua hari setelah gejala. Peneliti yakin tidak adanya pasien yg terkena dampak parah dalam penelitian disebabkan perawatan di rumah sakit sejak dini dan pemberian oseltamivir secepat mungkin pada sebagian pasien. (British Medical Journal)

Avian Influenza Mutation, H5N1 H5N1 is a type of avian influenza virus (bird flu virus) that has mutated through antigenic drift into dozens of highly pathogenic varieties. The first of these appeared in China in 1996 in birds and in Hong Kong in 1997 in Humans. This infection of humans coincided with an epizootic (an epidemic in nonhumans) of H5N1 influenza in Hong Kong's poultry population. This panzootic (a disease affecting animals of many species esp. over a wide area outbreak was stopped by the killing of the entire domestic poultry population within the territory. The name H5N1 refers to the subtypes of surface antigens present on the virus: hemagglutinin type 5 and neuraminidase type 1.

Influenza A virus, the virus that causes Avian flu. Transmission electron micrograph of negatively stained virus particles in late passage. (Source: Dr. Erskine Palmer, Centers for Disease Control and Prevention Public Health Image Library).

Colorized transmission electron micrograph of H5N1 (golden) grown in Madin-Darby canine kidney cells (green). (Source: C. Goldsmith, J. Katz and S. Zaki. Centers for Disease Control & Prevention Public Health Image Library. Image #1841.). As of November 1, 2005, 122 cases of infections in humans, resulting in 62 deaths, have been confirmed outside of China (see Human cases). Thirteen countries across Asia and Europe have been affected. Additionally, more than 120 million birds have died from infection or been killed to prevent further infections. Transmission and infection Infected birds pass on H5N1 through their saliva, nasal secretions, and feces. Other birds may pick up the virus through direct contact with these excretions or when they have contact with surfaces contaminated with this material. Because migratory birds are among the carriers of the H5N1 virus it may spread to all parts of the world. Past outbreaks of avian flu have often originated in crowded conditions in southeast and east Asia, where humans, pigs, and poultry live in close quarters. In these conditions a virus can mutate into a form that more easily infects humans. The majority of H5N1 flu cases have been reported in southeast and east Asia. Once an outbreak is detected, local authorities often order a mass slaughter of birds or animals affected. If this is done promptly, an outbreak of avian flu may be prevented. However, the United Nations (UN) World Health Organization (WHO) has expressed concern that not all

countries are reporting outbreaks as completely as they should. China, for example, is known to have officially denied past outbreaks of severe acute respiratory syndrome (SARS) and HIV. H5N1 infections in humans are generally caused by bird to human transmission of the virus. A few isolated cases of suspected human to human transmission exist, but there is no proof either way in those cases.

The current method of prevention in animal populations is to destroy infected animals as well as animals suspected of being infected. In southeast Asia, millions of domestic birds have been slaughtered to prevent the spread of the virus. The probability of a "humanized" form of H5N1 emerging through recombination in the body of a human co-infected with H5N1 and another influenza could be reduced by influenza vaccination of at-risk workers. It is not clear at this point whether vaccine production could be stepped up sufficiently to meet this demand. If an outbreak of pandemic flu does occur, its spread might be slowed by increasing hygiene in aircraft, and by examining airline cabin air filters for presence of H5N1 virus. The American Centers for Disease Control and Prevention advises travelers to areas of Asia where outbreaks of H5N1 have occurred to avoid poultry farms and animals in live food markets[2]. Travelers should also avoid surfaces that appear to be contaminated by feces from any kind of animal, especially poultry. There are several H5N1 vaccines for several of the H5N1 varieties. H5N1 continually mutates rendering them, so far for humans, of little use.

Since H5N1 is an influenza virus, symptoms similar to those of the common flu, such as fever, cough, sore throat, and sore muscles, can develop in infected humans. However, in more severe cases, pneumonia and respiratory failure can develop and eventually cause death. Patients with H5N1 avian influenza have rarely had conjunctivitis[3], unlike human cases of infection by the H7 virus. "The H5N1 virus causes an exaggerated response of cytokines (such as TNF-a), and this could result in a toxic-shock-like syndrome (including fever, chills, vomiting and headache), which ultimately results in death "In many diseases (including H5N1 in humans), a 'cytokine storm' [also called hypercytokinemia (sometimes spelled hypercytokinaemia)] is triggered by the infection. Cytokines are hormones that regulate the immune sytem. When released at the right time in the proper amounts, cytokines can help fight infections and regulate processes through out the body. But many cytokines are inflammatory and are damaging to the body if present in too high levels, or for too long. [...] But whatever it is called, this phenomenon is a type of inflammatory cascade. [...] Many inflammatory cascades have self limiting components - the release of an inflammatory agent often leads to the production of both antiinflammatory and inflammatory compounds. But as microbes evolve, they sometimes begin producing a mix of toxins that interfere with the control mechanisms of the immune system.

This seems to be the case for the deadly strains of avian influenza. The H5N1 virus is not only partially resistant to the cytokines that are involved in fighting viruses, but it also reduces the production of anti-inflammatory cytokines - in essence, it enhances the accelerator while impairing the brakes, and the immune system goes out of control and crashes."

"The 3 viral envelope proteins of influenza A virus are most medically relevant. The hemagglutinin (HA), neuraminidase (NA), and M2 are essential viral proteins targeted by host antibodies or antiviral drugs such as oseltamivir and rimantadine (46). The HA glycoprotein forms spikes at the surface of virions, mediating attachment to host cell sialoside receptors and subsequent entry by membrane fusion. The NA forms knoblike structures on the surface of virus particles and catalyzes their release from infected cells, allowing virus spread. The M2 is a transmembrane protein that forms an ion channel required for the uncoating process that precedes viral gene expression." Neuraminidase inhibitors are a class of drugs which act on a protein conserved in all influenza A viruses. Drugs of this type include zanamivir and oseltamivir, the latter being licensed for prophylaxis treatment in the United Kingdom. Oseltamivir, which "attacks the influenza virus and stops it from spreading" inside the user's body [7], is marketed by Roche as Tamiflu, and this brand has become the drug of choice for governments and organizations in their preparations for a possible H5N1 pandemic. In August 2005, Roche agreed to donate three million courses of Tamiflu to the World Health Organization, to be deployed by the WHO to contain a pandemic in its region of origin. Although Tamiflu is patented, international law gives governments wide freedom to issue compulsory licenses for lifesaving drugs. A further class of drugs, which include amantadine and rimantadine, target M2 protein, a proton channel found in the viral membrane. Unlike zanamivir and oseltamivir, these drugs are inexpensive and widely available and the WHO had initially planned to use them in efforts to combat a H5N1 pandemic. However, the potential of these drugs was considerably lessened when it was discovered that farmers in China has been administering amantadine to poultry with government encouragement and support since the early 1990s, against international livestock regulations; the result has been that the strain of the virus now circulating in South East Asia is largely resistant to the medication and hence significantly more dangerous to humans[8]. However, the strain of H5N1 spread throughout Northern China, Mongolia, Kazakhstan, Russia and Europe by wild birds in the summer of 2005 is not amantadine resistant.

Mutations and strains

"The influenza virus genome has remarkable plasticity because of a high mutation rate and its segmentation into 8 separate RNA molecules. This segmentation allows frequent genetic exchange by segment reassortment in hosts co-infected with 2 different influenza viruses." In July 2004, researchers led by H. Deng of the Harbin Veterinary Research Institute, Harbin, China and Professor Robert Webster of the St Jude Children's Research Hospital, Memphis, Tennessee, reported results of experiments in which mice had been exposed to 21 isolates of confirmed H5N1 strains obtained from ducks in China between 1999 and 2002. They found

"a clear temporal pattern of progressively increasing pathogenicity" Results reported by Dr. Webster in July 2005 reveal further progression toward pathogenicity in mice and longer virus shedding by ducks. In May 2005, the occurrence of avian influenza in pigs ("swine flu") in Indonesia was reported. Along with the continuing pattern of virus circulation in poultry, the occurrence in swine raises the level of concern about the possible evolution of the virus into a strain capable of causing a global human influenza pandemic. Health experts say pigs can carry human influenza viruses, which can combine (i.e. exchange homologous genome sub-units by genetic reassortment.) with the avian virus, swap genes and mutate into a form which can pass easily among humans. In July 2005, a death in Jakarta was the first confirmed human fatality in Indonesia. The deaths of two children, neither of whom were reported to have had close contact with poultry, further raised concerns of human-to-human transmission. [11] As of July 2005, most human cases of avian influenza in East Asia have been attributed to consumption of diseased poultry. Person-to-person transmission has not been unequivocally confirmed in the outbreaks in East Asia. On August 3, 2005, the WHO said it was following closely reports from China that at least 38 people have died and more than 200 others have been made ill by a swine-borne virus in Sichuan Province. Sichuan Province, where infections with Streptococcus suis have been detected in pigs in a concurrent outbreak, has one of the largest pig populations in China. The outbreak in humans has some unusual features and is being closely followed by the WHO. At that time, Chinese authorities say they have found no evidence of human-to-human transmission . On September 29, 2005, David Nabarro, the newly appointed Senior United Nations System Coordinator for Avian and Human Influenza, warned the world that an outbreak of avian influenza could kill 5 to 150 million people. Also, due to a bipartisan effort of the United States Senate, $4 billion dollars was appropriated to develop vaccines and treatments for Avian influenza. In 2004 and 2005, 118 people are known to have been infected with the H5N1 virus and 61 of them died. The mortality rate of this virus is as high as that of the virus H1N1 that caused the Spanish Flu of 1918, which killed over 20 million people world wide. One of the major differences between H1N1 of 1918 and the current H5N1 is the fact that the latter is not (yet) transmissible between humans. Until recently, that prevented the H5N1 virus from becoming a pandemic. Recent research of Taubenberger et al {Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG. Characterization of the 1918 influenza virus polymerase genes. Nature. 2005 Oct 6;437(7060):889-893} showed that the 1918 virus like H5N1 was an avian virus. Furthermore, Tumpey and colleagues {Tumpey TM, Basler CF, Aguilar PV, Zeng H, Solorzano A, Swayne DE, Cox NJ, Katz JM, Taubenberger JK, Palese P, GarciaSastre A. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science. 2005 Oct 7;310(5745):77-80} who reconstructed the H1N1 virus of 1918 come to the conclusion that it is especially the polymerase genes and the HA and NA genes that caused the extreme virulence of this virus. The sequences of the polymerase proteins (PA, PB1, and PB2) of the 1918 virus and subsequent human viruses differ by only 10 amino acids from the avian influenza viruses. Human forms of seven of the ten amino acids have already been identified in currently circulating H5N1. It is not unlikely that also the other mutations eventually will surface and make the H5N1 virus better suited for human-to-human transmission. Another important factor is the change of the HA protein to a binding

preference for alpha 2,6 sialic acid (the major form in the human respiratory tract). In avian virus the HA protein preferentially binds to alpha 2,3 sialic acid, which is the major form in the avian enteric tract. It has been shown that only a single amino acid change can result in the change of this binding preference. Altogether it seems that only a few mutations are needed to make the H5N1 avian influenza virus a pandemic virus like the one of 1918. "In Vietnam, scientists at the Ho Chi Minh Pasteur Institute who have been studying the genetic make up of H5N1 samples taken from people and poultry said it had undergone several mutations. 'There has been a mutation allowing the virus to (replicate) effectively in mammal tissue and become highly virulent,' the institute said on its Web site at"

Zanamivir, dipasarkan dengan nama produk Relenza oleh Glaxo Wellcome, perusahaan farmasi Inggris. Karena gugus quanidin, Zanamivir tidak bisa digunakan sebagai obat minum sebab senyawa bermuatan ion tidak dapat menembus dinding pembuluh darah untuk bisa diedarkan ke seluruh tubuh. Akibatnya, Relenza dikenal sebagai obat hirup. Walaupun sangat potensial bagi virus flu ganas yang tidak hanya menyerang saluran pernapasan dan bagi penderita anak-anak dan orang tua, obat hirup kuranglah cocok.

Ilmuwan-ilmuwan gabungan dari Inggris dan Vietnam, di dalam The New England Journal of Medicine, tanggal 22 Desember 2005, mempublikasikan penemuan terbarunya tentang kasus resistensi virus flu burung terhadap oseltamivir, satu-satunya bahan aktif obat yang dianggap cukup ampuh mengatasi flu burung saat ini. Virus yang resisten ini ditemukan pada isolat virus dari contoh darah seorang anak gadis yang teserang flu burung dan menjalani terapi dengan oseltamivir. Sementara pada contoh darah ibunya, yang meninggal akibat penyakit tersebut dalam keadaan belum sempat diobati intensif, tidak ditemukan resistensi virus tersebut (1). Menurut hasil penelitian tersebut, resistensi virus ditandai dengan adanya substitusi asam amino pada neuroaminidase. Neuroaminidase diketahui merupakan sebuah enzim antigen yang terdapat di permukaan virus flu burung. Substitusi asam amino ini menyebabkan virus lebih tahan terhadap oseltamivir. Neuroaminidase Inhibitor Oseltamivir bekerja dengan mekanisme neuroaminidase inhibitor sebagaimana yang pernah disinggung di dalam 29/9/2005 (Pertanyaan Seputar Flu Burung Bagian Ketiga, Red.). Neuroaminidase inhibitor bekerja dengan menginterfensi mekanisme pelepasan virus-virus baru dari sel-sel yang terinfeksi (menghambat replikasi perbanyakan virus) (2).


bekerja sebagai neuroaminidase inhibitor untuk mengatasi penyakit flu.(sma dg oseltamivir) diproduksi dan dipasarkan dalam bentuk inhaler.

Selain itu pula dikenal obat dengan mekanisme M2 inhibitor untuk mengatasi penyakit flu biasa, misalnya bahan aktif obat amantadine dan rimantadine. Bukan Kasus Resistensi yang Pertama Resistensi virus flu berbahan aktif obat dengan mekanisme neuroaminidase inhibitor dan M2 inhibitor ini bukanlah kasus yang pertama ditemukan. Sebelumnya pernah terdeteksi pada 4% pasien flu biasa yang mengkonsumsi neuroaminidase inhibitor oseltamivir, adanya mutasi virus flu tersebut menjadi lebih resisten (7). Demikian pula pada 80% anak-anak pasien flu biasa yang mengkonsumsi M2 inhibitor amantadine ditemukan kasus resistensi virus yang serupa (8). Jadi meskipun merebaknya kasus flu burung di tanah air sempat menimbulkan kepanikan, sebaiknya kita tetap waspada untuk tidak sembarangan meminum obat yang seharusnya dikonsumsi berdasarkan petunjuk dokter. Tentu saja hal ini demi menjaga seandainya terserang penyakit, tidak menjadi lebih parah akibat resistensi virus atau penyebab penyakit lainnya. Referensi: (1) de Jong, MD., dkk. 2005. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N. Eng. J. Med., 353(25):2667-2672. (2) Musconna, A. 2005. Review: Drug therapy; Neuraminidase Inhibitors for Influenza. N. Eng. J. Med., 353(13):1363-1373. (3) Hayden, FG., dkk. 1999. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. JAMA, 282(13):1240-1246. (4) Treanor, JJ., dkk. 2000. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. JAMA, 283(8):10571059. (5) Whitley, RJ., dkk. 2001. Oral oseltamivir treatment of influenza in children. Pediatr. Infect. Dis. J, 20(2):127-133. (6) Govorkova, EA., dkk. 2001. Comparison of efficacies of RWJ-270201, zanamivir, and oseltamivir against H5N1, H9N2, and other avian influenza viruses. Antimicrob. Agents & Chemother., 45(10) 2723-2732. (7) Gubareva, LV., dkk. 2001. Selection of influenza virus mutants in experimentally infected volunteers treated with oseltamivir. J. Infect. Dis., 183:523-631. (8) Shiraishi, K., dkk. 2003. High frequency of resistant viruses harboring different mutations in amantadine-treated children with influenza. J. Infect. Dis., 188:57-61.

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