Oseltamivir (oseltamivir) is applied to a neuraminidase inhibitor, which inhibits the effect of neuraminidase, influenza virus can be suppressed from mature host cells, thereby inhibiting the propagation of influenza virus in the human body to play a role in the treatment of influenza. Oseltamivir is based on the rational drug design of the structure of the success stories in the drug development process in a large number of applications means of computer-aided drug design, according to the three-dimensional structure of the target enzyme targeted specifically designed efficiency and low toxicity Strong inhibitors of neuraminidase. Roche Pharmaceutical Co., Ltd. is oseltamivir patent holder, and now they produce oseltamivir phosphate capsules (trade name Tamiflu, said the Chinese mainland, Hong Kong translation Tamiflu, Taiwan translated Tamiflu) is the market the only oseltamivir preparations. Between October 2005, due to the worldwide spread of bird flu, global _set_ off a wave of panic buying Tamiflu, Roche refused to open because of patent oseltamivir, Tamiflu sales restrictions were widespread acts condemned. ▲ development history Oseltamivir is a neuraminidase class of analogs of these drugs first appeared Glaxo SmithKline developed zanamivir. Since the physicochemical properties of the bar is not conducive to zanamivir bioabsorbable, and thus the low bioavailability of the drug, a single route of administration, patient compliance is poor. Oseltamivir is the tie on the basis of zanamivir, rational drug design based on molecular structure obtained neuraminidase natural substrate, and the spatial structure of neuraminidase of the catalytic center, following hiv integrase inhibitors After the agent is applied rational drug design means another successful drugs. Oseltamivir was first synthesized in 1996, 26 February 1998 granted a U.S. patent, in October 1999 for the first time launched in Sweden, and then into Canada, the EU and U.S. markets in 2002 allowed China launched. December 2005, the findings of Oxford University shows the bird flu virus began to develop resistance to Tamiflu. December 22, urged Roche to increase the dose of Tamiflu against avian influenza. ▲ mechanism Wei role of oseltamivir target is located in the influenza virus neuraminidase surface. Neuraminidase plays an important role in the life cycle of the virus, the influenza virus replication and expression in a host cell after assembly, in the form of protruding budding host cells, but the host cell to thrombin - sialic acid connected as neuraminidase substrates of sialic acid, sialic acid can be catalyzed hydrolysis, releasing the mature viral particles contact between host cells, so that it can move freely invade other healthy host cells. The inhibition of neuraminidase activity may prevent the release of virus particles, cutting strand viral proliferation, and therefore can be a neuraminidase drug target for treatment of influenza. It has long been gained neuraminidase three-dimensional structure by x-ray diffraction of the way and get the neuraminidase active site of the relevant information. Research shows that the activity of neuraminidase center pocket 11 from the highly conserved amino acid sequence consisting of the pocket entrance of the distribution of the active region and a hydrophobic region of a concentration of positive charge, the bottom of the pocket is a negative charge concentrated cracks . This structure can be active pocket well with its natural substrate sialic acid. Designer with a larger alkyl group substituted with a sialic acid glycerol, using the structure and activity of a hydrophobic pocket in the combined area; 3-substituted amino group of the hydroxyl group of the sialic acid, and thereby the bottom of the active pocket binding negatively charged center; carboxylic acid is an active center of the positive portion of the binding pocket of the structure of the mouth, the free carboxylic acid in ethanol oseltamivir closed designs used in this structure of the target enzyme itself, did not inhibit activity, but because the polarity of the closed end of a carboxylic acid, can enhance the absorption of the drug molecule, to obtain a better pharmacokinetic properties, the catalytic hydrolysis in vivo, the free carboxylic acid are re-released, the corresponding display inhibitory activity, This design is called in medicinal chemistry before becoming drug. ▲ Indications and Dosage Waite heterosexual oseltamivir neuraminidase inhibition of influenza by the h5n1, h9n2 subtype of influenza virus and other treatment and prevention role. According to information published on the website Roche taking oseltamivir within 24 hours after the on_set_ of his patients Wei, the course will be shortened by 30% -40%, the disease will reduce by 25%, as a preventive medication, oseltamivir against influenza virus protection rate exposure by between 80% -90%. Now listed oseltamivir has two forms, one is a capsule, one is oral suspension. Capsule size is 75mg, the solvent is water the suspension, the specification is 12mg/ml. Manufacturer's recommended dose for the treatment of influenza, two days starting from the on_set_ of symptoms in adults and adolescents (13 years) taken twice a day, every 75mg, five consecutive days. Infants under one year old has not been used in the recommended dosage. For the prevention of influenza for adults and adolescents (13 years and older) daily doses of 75mg, taking seven days in a row, you can get six weeks of protection, taking longer time, the cumulative dose, the longer protection time. ▲ adverse reactions Roche submitted in the U.S. Federal Food and Drug Administration application materials indicated that oseltamivir major adverse reactions appear as gastrointestinal discomfort including nausea, vomiting, diarrhea, abdominal pain, followed by respiratory adverse reactions, including bronchitis, coughing, etc., in addition to the central nervous system adverse reactions, such as dizziness, headache, insomnia, fatigue. In January 2004, fda also issued for oseltamivir consumer alert, claiming that less than 1 year old children are not fully developed blood-brain barrier, oseltamivir used in young children can cause brain drug concentration is too high, a potential security issues. 2005 Japanese media reported that Japanese youth suicide after taking oseltamivir and mental abnormal reaction, after which the Japanese have reported dozens of cases of such adverse reactions, then reprinted in media around the world reported that aroused public concern. Fda to report on this reaction in November 2005, that there is no evidence that oseltamivir can cause mental disorders, adverse reactions after Japanese media reported cases of Department of Mass effect caused by the psychological implications of mass chest disease. ▲ pharmacokinetic parameters Since the formation of a prodrug, oseltamivir have better pharmacokinetic properties, oral absorption after 30 minutes, 75% in the form of the carbonate into the circulation, but only 5% of the salt into the minor loop. 2 to 3 hours after peak plasma concentration, and its distribution in the body can be directed to the lungs, bronchi, sinuses, middle ear and other parts. Oseltamivir in the body by the kidneys in the form of acid excretion original drug, elimination half-life 6-10 hours. ▲ Tamiflu with Roche Roche is oseltamivir patent holder, the production of oseltamivir phosphate capsules Tamiflu is the only oseltamivir preparations. And Roche is not well-known because of this drug when Rehuoshangshen. Roche is also the history of his business because the control of vitamin raw materials markets have suffered heavy fines EEC. For South Asia's bird flu outbreak, the company has not taken measures to increase the supply of drugs in South Asia in the early development of the epidemic, by some governments in South and Southeast Asia complain. ① disinformation event In early 2003, the outbreak of sars epidemic caused by a coronavirus in southern China, Shanghai Roche claimed that the information released to the public: the culprit is caused by sars bird flu virus, Roche produces Tamiflu is the only known to have a therapeutic effect of bird flu drugs. Guangzhou, which triggered a wave of panic buying Tamiflu and expanded to southern China. After investigation, "Southern Metropolis Daily" reporter found that Roche has not yet been time to oseltamivir inhibit the activity of avian flu clinical trials, the Southern Metropolis Daily reported at the same time make, related information will be reported in Guangdong Province Public Security Bureau. At that time, the Chinese government strictly controlled information sars epidemic, fearing social unrest, Roche spreading false information on the behavior of the Guangdong market has caused panic buying of Tamiflu, therefore causing the attention of the public security department, the Southern Metropolis Daily report, the Guangdong Provincial Public Security Hall then for Roche to investigate. The incident was later named the 2003 China top ten pharmaceutical companies media public relations crisis. ② avian flu and patent licensing dispute Between October 2005 global epidemic of avian influenza signs, the global consumption of Tamiflu increased significantly. This has been tightly controlled Roche Tamiflu production, even confidential address Tamiflu production lines, and to prohibit the reporter interviewed after the avian flu scare struck Roche announced that restrict the sale of Tamiflu to ensure that once the flu outbreak, to have adequate sources of supply patients the move was opposed by some organizations. Roche group also pointed out that oseltamivir should abandon the patent monopoly, expanding global production capacity of this drug in order to cope with a possible avian flu epidemic. In Asia, India, Taiwan enterprises and research institutions have announced the successful synthesis of oseltamivir, and announced once the bird flu epidemic out of control, will produce its own oseltamivir preparations. Under pressure from all sides, Roche announced the partial liberalization patent monopoly, allowing authorized factory production of oseltamivir. November 2005, the ROC government Department of Health in consultation with the opening Roche oseltamivir production rights to Taiwanese manufacturers, after several unsuccessful negotiations, the Department of Health to the Ministry of Economic Affairs Intellectual Property Office in charge of patent applications in accordance with ROC "patent Law "Article 76 mandatory authorization. In November 25, 2005, the Intellectual Property Office of the Department of Health agreed to the application, which is the world's first case of Tamiflu drugs for compulsory licensing orders. December 2005, Roche opened production rights to the Shanghai Pharmaceutical Group. March 16, 2006, Roche duly authorized Shenzhen East Sunshine Industrial Development Co., Ltd. (East Sunshine) in China producing oseltamivir tradename military 科奥韦. ③ production processes rumors October 2005 bird flu scare sweeping the globe, because the efficacy of Tamiflu bird flu drugs and become a star, then make some Chinese media reports, claiming that the Department of compounds extracted from Chinese star anise Tamiflu through scouring, due to China's octagonal in short supply, Tamiflu production capacity is limited. The spread of such claims cause some people buying octagonal mainland and Taiwan to cope with the possible arrival of bird flu. But in fact, oseltamivir is not anise extract, but its synthetic route system once the plants start shikimic acid metabolites, shikimic acid nor anise unique ingredients, as a plant metabolite, which exists in almost all higher plants and flavonoids, alkaloids and other common plant secondary metabolite biosynthesis starting material. Affected due to insufficient supply of medicine oseltamivir capacity argument is the result of media speculation.
Translated by Google
No. 2
Oseltamivir (Oseltamivir) is applied to a neuraminidase inhibitor, which inhibits the effect of neuraminidase, influenza virus can be suppressed from mature host cells, thereby inhibiting the propagation of influenza virus in the human body to play a role in the treatment of influenza. Oseltamivir is based on the rational drug design of the structure of the success stories in the drug development process in a large number of applications means of computer-aided drug design, according to the three-dimensional structure of the target enzyme targeted specifically designed efficiency and low toxicity Strong inhibitors of neuraminidase. Roche Pharmaceutical Co., Ltd. is oseltamivir patent holder, and now they produce oseltamivir phosphate capsules (trade name Tamiflu, said the Chinese mainland, Hong Kong translation Tamiflu, Taiwan translated Tamiflu) is the market the only oseltamivir preparations. Between October 2005, due to the worldwide spread of bird flu, global _set_ off a wave of panic buying Tamiflu, Roche refused to open because of patent oseltamivir, Tamiflu sales restrictions were widespread acts condemned. ▲ development history Oseltamivir is a neuraminidase class of analogs of these drugs first appeared Glaxo SmithKline developed zanamivir. Since the physicochemical properties of the bar is not conducive to zanamivir bioabsorbable, and thus the low bioavailability of the drug, a single route of administration, patient compliance is poor. Oseltamivir is the tie on the basis of zanamivir, rational drug design based on molecular structure obtained neuraminidase natural substrate, and the spatial structure of neuraminidase catalytic center, following the inhibition of HIV integrase After the agent is applied rational drug design means another successful drugs. Oseltamivir was first synthesized in 1996, 26 February 1998 granted a U.S. patent, in October 1999 for the first time launched in Sweden, and then into Canada, the EU and U.S. markets in 2002 allowed China launched. December 2005, the findings of Oxford University shows the bird flu virus began to develop resistance to Tamiflu. December 22, urged Roche to increase the dose of Tamiflu against avian influenza. ▲ mechanism Wei role of oseltamivir target is located in the influenza virus neuraminidase surface. Neuraminidase plays an important role in the life cycle of the virus, the influenza virus replication and expression in a host cell after assembly, in the form of protruding budding host cells, but the host cell to thrombin - sialic acid connected as neuraminidase substrates of sialic acid, sialic acid can be catalyzed hydrolysis, releasing the mature viral particles contact between host cells, so that it can move freely invade other healthy host cells. The inhibition of neuraminidase activity may prevent the release of virus particles, cutting strand viral proliferation, and therefore can be a neuraminidase drug target for treatment of influenza. It has long been gained neuraminidase three-dimensional structure by X-ray diffraction of the way and get the neuraminidase active site of the relevant information. Research shows that the activity of neuraminidase center pocket 11 from the highly conserved amino acid sequence consisting of the pocket entrance of the distribution of the active region and a hydrophobic region of a concentration of positive charge, the bottom of the pocket is a negative charge concentrated cracks . This structure can be active pocket well with its natural substrate sialic acid. Designer with a larger alkyl group substituted with a sialic acid glycerol, using the structure and activity of a hydrophobic pocket in the combined area; 3-substituted amino group of the hydroxyl group of the sialic acid, and thereby the bottom of the active pocket binding negatively charged center; carboxylic acid is an active center of the positive portion of the binding pocket of the structure of the mouth, the free carboxylic acid in ethanol oseltamivir closed designs used in this structure of the target enzyme itself, did not inhibit activity, but because the polarity of the closed end of a carboxylic acid, can enhance the absorption of the drug molecule, to obtain a better pharmacokinetic properties, the catalytic hydrolysis in vivo, the free carboxylic acid are re-released, the corresponding display inhibitory activity, This design is called in medicinal chemistry before becoming drug. ▲ Indications and Dosage Waite heterosexual oseltamivir neuraminidase inhibition of influenza from the H5N1, H9N2 and other influenza virus subtypes caused by treatment and prevention role. According to information published on the website Roche taking oseltamivir within 24 hours after the on_set_ of his patients Wei, the course will be shortened by 30% -40%, the disease will reduce by 25%, as a preventive medication, oseltamivir against influenza virus protection rate exposure by between 80% -90%. Now listed oseltamivir has two forms, one is a capsule, one is oral suspension. Capsule size is 75mg, the solvent is water the suspension, the specification is 12mg/mL. Manufacturer's recommended dose for the treatment of influenza, two days starting from the on_set_ of symptoms in adults and adolescents (13 years) taken twice a day, every 75mg, five consecutive days. Infants under one year old has not been used in the recommended dosage. For the prevention of influenza for adults and adolescents (13 years and older) daily doses of 75mg, taking seven days in a row, you can get six weeks of protection, taking longer time, the cumulative dose, the longer protection time. ▲ adverse reactions Roche submitted in the U.S. Federal Food and Drug Administration application materials indicated that oseltamivir major adverse reactions appear as gastrointestinal discomfort including nausea, vomiting, diarrhea, abdominal pain, followed by respiratory adverse reactions, including bronchitis, coughing, etc., in addition to the central nervous system adverse reactions, such as dizziness, headache, insomnia, fatigue. In January 2004, FDA also issued for oseltamivir consumer alert, claiming that less than 1 year old children are not fully developed blood-brain barrier, oseltamivir used in young children can cause brain drug concentration is too high, a potential security issues. 2005 Japanese media reported that Japanese youth suicide after taking oseltamivir and mental abnormal reaction, after which the Japanese have reported dozens of cases of such adverse reactions, then reprinted in media around the world reported that aroused public concern. FDA to report on this reaction in November 2005, that there is no evidence that oseltamivir can cause mental disorders, adverse reactions after Japanese media reported cases of Department of Mass effect caused by the psychological implications of mass chest disease. ▲ pharmacokinetic parameters Since the formation of a prodrug, oseltamivir have better pharmacokinetic properties, oral absorption after 30 minutes, 75% in the form of the carbonate into the circulation, but only 5% of the salt into the minor loop. 2 to 3 hours after peak plasma concentration, and its distribution in the body can be directed to the lungs, bronchi, sinuses, middle ear and other parts. Oseltamivir in the body by the kidneys in the form of acid excretion original drug, elimination half-life 6-10 hours. ▲ Tamiflu with Roche Roche is oseltamivir patent holder, the production of oseltamivir phosphate capsules Tamiflu is the only oseltamivir preparations. And Roche is not well-known because of this drug when Rehuoshangshen. Roche is also the history of his business because the control of vitamin raw materials markets have suffered heavy fines EEC. For South Asia's bird flu outbreak, the company has not taken measures to increase the supply of drugs in South Asia in the early development of the epidemic, by some governments in South and Southeast Asia complain. ① disinformation event In early 2003, the outbreak of SARS epidemic caused by a coronavirus in southern China, Shanghai Roche claimed that the information released to the public: the culprit is the cause of SARS bird flu virus, Roche produces Tamiflu is the only known to have a therapeutic effect of bird flu drugs. Guangzhou, which triggered a wave of panic buying Tamiflu and expanded to southern China. After investigation, "Southern Metropolis Daily" reporter found that Roche has not yet been time to oseltamivir inhibit the activity of avian flu clinical trials, the Southern Metropolis Daily reported at the same time make, related information will be reported in Guangdong Province Public Security Bureau. At that time, the Chinese government strictly controlled information SARS epidemic, fearing social unrest, Roche spreading false information on the behavior of the Guangdong market has caused panic buying of Tamiflu, therefore causing the attention of the public security department, the Southern Metropolis Daily report, the Guangdong Provincial Public Security Hall then for Roche to investigate. The incident was later named the 2003 China top ten pharmaceutical companies media public relations crisis. ② avian flu and patent licensing dispute Between October 2005 global epidemic of avian influenza signs, the global consumption of Tamiflu increased significantly. This has been tightly controlled Roche Tamiflu production, even confidential address Tamiflu production lines, and to prohibit the reporter interviewed after the avian flu scare struck Roche announced that restrict the sale of Tamiflu to ensure that once the flu outbreak, to have adequate sources of supply patients the move was opposed by some organizations. Roche group also pointed out that oseltamivir should abandon the patent monopoly, expanding global production capacity of this drug in order to cope with a possible avian flu epidemic. In Asia, India, Taiwan enterprises and research institutions have announced the successful synthesis of oseltamivir, and announced once the bird flu epidemic out of control, will produce its own oseltamivir preparations. Under pressure from all sides, Roche announced the partial liberalization patent monopoly, allowing authorized factory production of oseltamivir. November 2005, the ROC government Department of Health in consultation with the opening Roche oseltamivir production rights to Taiwanese manufacturers, after several unsuccessful negotiations, the Department of Health to the Ministry of Economic Affairs Intellectual Property Office in charge of patent applications in accordance with ROC "patent Law "Article 76 mandatory authorization. In November 25, 2005, the Intellectual Property Office of the Department of Health agreed to the application, which is the world's first case of Tamiflu drugs for compulsory licensing orders. December 2005, Roche opened production rights to the Shanghai Pharmaceutical Group. March 16, 2006, Roche duly authorized Shenzhen East Sunshine Industrial Development Co., Ltd. (East Sunshine) in China producing oseltamivir tradename military 科奥韦. ③ production processes rumors October 2005 bird flu scare sweeping the globe, because the efficacy of Tamiflu bird flu drugs and become a star, then make some Chinese media reports, claiming that the Department of compounds extracted from Chinese star anise Tamiflu through scouring, due to China's octagonal in short supply, Tamiflu production capacity is limited. The spread of such claims cause some people buying octagonal mainland and Taiwan to cope with the possible arrival of bird flu. But in fact, oseltamivir is not anise extract, but its synthetic route system once the plants start shikimic acid metabolites, shikimic acid nor anise unique ingredients, as a plant metabolite, which exists in almost all higher plants and flavonoids, alkaloids and other common plant secondary metabolite biosynthesis starting material. Affected due to insufficient supply of medicine oseltamivir capacity argument is the result of media hype.
Translated by Google
Drug Encyclopedia
Drug Name (Including trade name, generic name) Oseltamivir Dosage General dosage: oseltamivir phosphate oral dose is recommended every 1, 2 times a day for 5 days. Flu symptoms begin in the first day or the next day should begin treatment. Oseltamivir phosphate can be separated from service with the same clothes or food. For some patients with eating while taking the drug can enhance tolerance. Patients with renal insufficiency: creatinine clearance greater than 30 mL / minute who do not need to adjust the dose. Creatinine clearance less than 30 mL / minute, recommended dose is reduced each time a once a day for 5 days. Not in creatinine clearance less than 10 mL / min in patients with renal failure who did oseltamivir phosphate research, the application of oseltamivir phosphate must be careful in this crowd. Hepatic dysfunction: Patients with hepatic dysfunction does not require dose adjustment. Older people: the elderly do not need to adjust the dose. Children: oseltamivir phosphate data on safety and efficacy studies in pediatric patients have not yet been fully established. At present, only limited pharmacokinetic data for children. Pharmacological effects is oseltamivir phosphate prodrug of the active metabolite body, its active metabolite is a potent and _select_ive inhibitor of influenza virus neuraminidase. Neuraminidase activity of newly formed virus particles from infected cells and release of infectious virus in the body is critical to further spread. Active metabolites of drugs inhibiting neuraminidase influenza A and B viruses. Vitro at low nanomolar concentration that is inhibitory effect. Activity was observed in vitro inhibition of influenza virus growth metabolite in vivo also was observed to inhibit influenza virus replication and pathogenicity. This product by inhibiting the release of virus from infected cells, thereby reducing the spread of influenza A or B virus. In Phase III clinical trials, patients from the on_set_ of clinical symptoms after starting with oseltamivir phosphate treatment, not to exceed 60 hours. This treatment significantly shorten the duration of flu symptoms and signs of the time, up to 45 hours to reduce. With placebo, patients diagnosed with influenza taking oseltamivir phosphate can reduce the severity of the disease is about 40%. More importantly, oseltamivir phosphate, reducing the incidence and antibiotic treatment to those of influenza-related complications in healthy young adult population reduced by 50%, 75% reduction in the elderly population. These complications include bronchitis, pneumonia and sinusitis. And the study of naturally acquired influenza laboratories obtained showed: Application of oseltamivir phosphate did not harm normal human antibody response to infection. Subjects antibody response to influenza vaccine does not affect oseltamivir phosphate treatment by. The possibility of viral resistance to give in-depth research. Clinical isolates, the incidence of viral resistance depends subtypes of about 2%. Resistant virus carriers can be as normal as clear the virus, and no worsening of clinical signs. Resistant genotypes no advantage at all, and human infection is reduced. Indications for treatment of influenza. Adverse reactions in clinical studies of a group of influenza A total of 943 patients were income oseltamivir phosphate groups, the most frequently reported adverse reactions are nausea and vomiting. Symptoms are transient, often occurs when taking the first dose. The vast majority of patients did not result in adverse reactions to disable study drug. Clinical Study on Treatment of adult phase III, there are some in the incidence of adverse reactions to oseltamivir phosphate group was significantly higher than in the placebo group. In adults (including the elderly a small part), each administered as a twice daily, the incidence of adverse reactions than 1% (Putting aside whether it related to the drug) had vomiting, nausea (not vomiting), insomnia, headaches and abdominal pain. Details are as follows: Vomiting: placebo (N = 475) - 15 cases (3.2%), oseltamivir group (N = Formulation Capsules: 98.5mg precautions disabled oseltamivir phosphate or allergy to any component of the drug. Creatinine clearance less than 30 mL / min in patients suggested a dose adjustment. There is no research data to provide renal failure (creatinine clearance less than 10 mL / min) medication experience. So be careful when the crowd medication. Pregnant and lactating women use: Animal reproduction studies conducted on rats and rabbits, no teratogenic drugs was observed. Also carried out on rats reproductive toxicity studies, no dose oseltamivir is not observed impact of drugs on the fertility of rats. The amount of the drug in rats accepted rabbit embryos are maternal and about 15-20% of females. There is currently a lack of sufficient data to evaluate pregnant women after taking oseltamivir phosphate Wei drugs cause fetal malformations or fetal toxicity potential. If not confirm the potential benefit outweighs the potential risk, not recommended for pregnant women given oseltamivir phosphate. Lactation in rats, oseltamivir and its active metabolite can be secreted from the milk. It is not known who the two will not be discharged from the milk. Preliminary data from animal tests concluded that human milk is estimated that about 0.01 mg per day of oseltamivir, 0.3 mg of its active metabolite. Confirm the drug only when the potential benefits outweigh the potential risk of nursing mothers to breastfeed infants, before they can use oseltamivir phosphate. Elderly patients: elderly patients do not need to adjust the dose. [Storage / validity] below 30 ℃ storage. Valid for 2 years.