Influenza is an acute respiratory disease caused by the influenza virus. Each year, it causes a significant disease burden, especially in older adults. Furthermore, influenza pandemics occasionally occur because of antigenic change. Common signs and symptoms of influenza include fever, cough, sore throat, headache, myalgia, and runny nose. Severe cases may progress to pneumonia, which causes shortness of breath, tachycardia, hypotension, and the need for supportive respiratory interventions. Mild cases are self-limited and supportive care is sufficient. Antiviral treatment shortens the clinical course if it is administered within 48 hours from the onset of disease. Neuraminidase inhibitors, such as oseltamivir, zanamivir, and peramivir, are widely used. Although annual vaccination is the best means of prevention, its effectiveness can vary from year to year and among different age and risk groups.
Adult ; Cough ; Dyspnea ; Fever ; Headache ; Humans ; Hypotension ; Influenza, Human ; Myalgia ; Neuraminidase ; Nose ; Orthomyxoviridae ; Oseltamivir ; Pandemics ; Pharyngitis ; Pneumonia ; Tachycardia ; Vaccination ; Zanamivir

Influenza causes variable epidemics annually and imposes public health problems and socioeconomic burden. They cause epidemic acute respiratory disease, characterized by fever, cough and systemic symptoms. The annual epidemics of seasonal influenza can affect any age group and result in serious illness or death, particularly in high risk populations such as adults > 65 years old, children < 2 years old and those with chronic medical condition at any age. Three types (A, B, and C) are recognized as well as many subtypes within the type A. New influenza A virus subtypes sporadically emerge in humans to cause widespread disease or pandemics. Antiviral therapy with oseltamivir or zanamivir is available and shorten the duration of illness and reduce the rate of complications. Influenza vaccines are effective in the prevention of influenza illness, although improved vaccines are needed.
Adult ; Child ; Cough ; Fever ; Humans ; Influenza A virus ; Influenza Vaccines ; Influenza, Human* ; Oseltamivir ; Pandemics ; Public Health ; Seasons ; Vaccines ; Zanamivir

OBJECTIVETo analyze the susceptibility of influenza A (H3N2) viruses to neuraminidase inhibitors during 2011-2012 in Mainland China.

METHODSAll the tested viruses were obtained from the Chinese National Influenza Surveillance Network, which covers 31 provinces in mainland China, including 408 network laboratories and 554 sentinel hospitals. In total 1 903 viruses were selected with isolation date from January 1, 2011 to December 31, 2012 in Mainland China, among these viruses, 721 were confirmed to be influenza A (H3N2) virus by Chinese National Influenza Center and tested for the susceptibility to oseltamivir and zanamivir using chemiluminescence-based assay. The neuraminidase inhibitor sensitive reference virus A/Washington/01/2007 (119E) and oseltamivir resistant virus A/Texas/12/2007 (E119V) were used as control in this study. The t -test was used to compare the difference of NAI susceptibility of viruses isolated from different years.

RESULTSThe half maximal inhibitory concentration (IC₅₀) of A/Washington/01/2007 for oseltamivir and zanamivir was (0.10 ± 0.02) and (0.30 ± 0.05) nmol/L, respectively. The IC₅₀ of A/Texas/12/2007 for oseltamivir and zanamivir was (4.27 ± 1.60) and (0.20 ± 0.03) nmol/L, respectively. Among the 721 influenza A (H3N2) viruses, 132 influenza A (H3N2) viruses were isolated in 2011 and 589 influenza A (H3N2) viruses were isolated in 2012. The IC50 for oseltamivir ranged from 0.04 to 0.62 nmol/L for viruses isolated in 2011 and ranged from 0.02 to 0.95 nmol/L for viruses in 2012, and the IC₅₀ of all the viruses tested was within 10-fold IC₅₀ (1.0 nmol/L) of the neuraminidase inhibitor sensitive reference virus A/Washington/01/2007. The IC50 of zanamivir ranged from 0.12 to 0.80 nmol/L for viruses in 2011 and ranged from 0.04 to 0.72 nmol/L for viruses in 2012, and was within 10-fold IC₅₀ (3.0 nmol/L) of the neuraminidase inhibitor sensitive reference virus A/Washington/01/2007.

CONCLUSIONThe influenza A(H3N2) viruses isolated during 2011-2012 in Mainland China were tested to be sensitive to oseltamivir and zanamivir.

Antiviral Agents ; China ; Drug Resistance, Viral ; Enzyme Inhibitors ; Epidemiological Monitoring ; Humans ; Influenza A Virus, H3N2 Subtype ; Influenza, Human ; Neuraminidase ; Oseltamivir ; Zanamivir

This study aimed to investigate the drug susceptibility of wild-type and mutant avian influenza A (H7N9) virus neuraminidase (NA) to oseltamivir and zanamivir. Codon optimized DNA of H7N9 (A/ Hangzhou/1/2013) NA was synthesized and constructed into the pcDNA3.1/His vector (NA(H7N9-WT)). Mutant NA(H7N9-H274Y) and NA(H7N9-R292K) plasmids were constructed by directed mutagenesis PCR using NA(H7N9-WT) plasmid as the template followed by sequencing. NA plasmids were transfected into 293T cells and cell lysates containing NAs were collected 48 h post-transfection. Wild-type and mutant NAs were analyzed by Western blotting and their activities were tested by the 4-MUNANA-based assay. All three NAs were expressed and enzymatic activities were confirmed. The effects of oseltamivir and zanamivir on all three NAs were then tested. It showed that the half maximal inhibitory concentrations (IC50s) of oseltamivir carboxylate on NA(H7N9-WT), NA(H7N9-H274Y) and NA(H7N9-R292K) were 1.6 nM, 15.1 nM, and > 1 000 nM with fold changes of 9 and > 625, respectively. The IC50 values of zanamivir on NA(H7N9-WT), NA(H7N9-H274Y), and NA(H7N9-R292K) were 1.1 nM, 1.4 nM, and 38.0 nM with fold changes of 1.3 and 34, respectively. These results indicated that oseltamivir and zanamivir could significantly inhibit NA(H7N9-WT). NA(H7N9-R292K) showed high-level resistance to both drugs (34-fold and 625-fold) and NA(H7N9-H274Y) was sensitive to both (1.3-fold and 9-fold). These results indicated that both oseltamivir and zanamivir could be used for patients infected with the H7N9 virus. However, when patients carried the H7N9 virus with a NA R292K mutation, other medications would be preferred over oseltamivir or zanamivir.
Antiviral Agents ; pharmacology ; Humans ; Influenza A Virus, H7N9 Subtype ; drug effects ; enzymology ; genetics ; Influenza, Human ; virology ; Microbial Sensitivity Tests ; Mutation ; Neuraminidase ; antagonists & inhibitors ; genetics ; metabolism ; Oseltamivir ; pharmacology ; Viral Proteins ; antagonists & inhibitors ; genetics ; metabolism ; Zanamivir ; pharmacology

The objective of this study was to enhance the oral bioavailability (BA) of zanamivir (ZMR) by increasing its intestinal permeability using permeation enhancers (PE). Four different classes of PEs (Labrasol(R), sodium cholate, sodium caprate, hydroxypropyl beta-cyclodextrin) were investigated for their ability to enhance the permeation of ZMR across Caco-2 cell monolayers. The flux and Papp of ZMR in the presence of sodium caprate (SC) was significantly higher than other PEs in comparison to control, and was selected for further investigation. All concentrations of SC (10-200 mM) demonstrated enhanced flux of ZMR in comparison to control. The highest flux (13 folds higher than control) was achieved for the formulation with highest SC concentration (200 mM). The relative BA of ZMR formulation containing SC (PO-SC) in plasma at a dose of 10 mg/kg following oral administration in rats was 317.65% in comparison to control formulation (PO-C). Besides, the AUC0-24 h of ZMR in the lungs following oral administration of PO-SC was 125.22 +/- 27.25 ng hr ml(-1) with a Cmax of 156.00 +/- 24.00 ng/ml reached at 0.50+/-0.00 h. But, there was no ZMR detected in the lungs following administration of control formulation (PO-C). The findings of this study indicated that the oral formulation PO-SC containing ZMR and SC was able to enhance the BA of ZMR in plasma to an appropriate amount that would make ZMR available in lungs at a concentration higher (>10 ng/ml) than the IC50 concentration of influenza virus (0.64-7.9 ng/ml) to exert its therapeutic effect.
Administration, Oral ; Animals ; Biological Availability* ; Caco-2 Cells ; Humans ; Influenza, Human ; Inhibitory Concentration 50 ; Lung* ; Orthomyxoviridae ; Permeability ; Plasma* ; Rats* ; Sodium ; Sodium Cholate ; Zanamivir*

PURPOSE: There was a global increase in the prevalence of oseltamivir-resistant influenza viruses during the 2007-2008 influenza season. This study was conducted to investigate the occurrence and characteristics of oseltamivir-resistant influenza viruses during the 2007-2008 and 2008-2009 influenza seasons among patients who were treated with oseltamivir (group A) and those that did not receive oseltamivir (group B). METHODS: A prospective study was conducted on 321 pediatric patients who were hospitalized because of influenza during the 2007-2008 and 2008-2009 influenza seasons. Drug resistance tests were conducted on influenza viruses isolated from 91 patients. RESULTS: There was no significant difference between the clinical characteristics of groups A and B during both seasons. Influenza A/H1N1, isolated from both groups A and B during the 2007-2008 and 2008-2009 periods, was not resistant to zanamivir. However, phenotypic analysis of the virus revealed a high oseltamivir IC50 range and that H275Y substitution of the neuraminidase (NA) gene and partial variation of the hemagglutinin (HA) gene did not affect its antigenicity to the HA vaccine even though group A had a shorter hospitalization duration and fewer lower respiratory tract complications than group B. In addition, there was no significant difference in the clinical manifestations between oseltamivir-susceptible and oseltamivir-resistant strains of influenza A/H1N1. CONCLUSION: Establishment of guidelines to efficiently treat influenza with oseltamivir, a commonly used drug for treating influenza in Korean pediatric patients, and a treatment strategy with a new therapeutic agent is required.
Child ; Drug Resistance ; Hemagglutinins ; Hospitalization ; Humans ; Influenza, Human ; Inhibitory Concentration 50 ; Neuraminidase ; Orthomyxoviridae ; Oseltamivir ; Prevalence ; Prospective Studies ; Respiratory System ; Seasons ; Viruses ; Zanamivir

BACKGROUNDIt is the first multicenter clinical study in China to investigate zanamivir use among Chinese adolescents and adults with influenza-like illness (ILI) since 2009, when inhaled zanamivir (RELENZA(®)) was marketed in China.

METHODSAn uncontrolled open-label, multicentre study to evaluate the antiviral activity, and safety of inhaled zanamivir (as Rotadisk via Diskhaler device); 10 mg administered twice daily for 5 days in subjects ≥ 12 years old with ILI. Patients were enrolled within 48 hours of onset and followed for eight days. Patients were defined as being influenza-positive if the real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) test had positive results.

RESULTSA total of 400 patients ≥ 12 years old were screened from 11 centers in seven provinces from March 2010 to January 2011. Three hundred and ninety-two patients who took at least one dose of zanamivir were entered into the safety analysis. The mean age was 33.8 years and 50% were male. Cardiovascular diseases and diabetes were the most common comorbidities. All the reported adverse events, such as rash, nasal ache, muscle ache, nausea, diarrhea, headache, occurred in less than 1% of subjects. Mild sinus bradycadia or arrhythmia occurred in four subjects (1%). Most of the adverse events were mild and did not require any change of treatment. No severe adverse events (SAE) or fatal cases were reported. Bronchospasm was found in a 38 years old woman whose symptoms disappeared after stopping zanamivir and without additional treatment. All the 61 influenza virus isolates (43 before enrollment, 18 during treatment) proved to be sensitive to zanamivir.

CONCLUSIONSZanamivir is well tolerated by Chinese adolescents and adults with ILIs. There is no evidence for the emergence of drug-resistant isolates during treatment with zanamivir.

Adolescent ; Adult ; Antiviral Agents ; administration & dosage ; adverse effects ; therapeutic use ; Female ; Humans ; Influenza, Human ; drug therapy ; Male ; Middle Aged ; Treatment Outcome ; Zanamivir ; administration & dosage ; adverse effects ; therapeutic use

Influenza virus RNA-dependent RNA polymerase (RdRP) is essential for replication and expression of influenza virus genome. Viral genomic sequences encoding RdRP are highly conservative, thus making it a potential anti-influenza drug target. A cell-based influenza RdRP inhibitor screening assay was established by a luciferase reporter system to analyze the activity of RdRP. Specificity study and statistic analysis showed that the screening assay is sensitive and reproducible.
Amantadine ; pharmacology ; Antiviral Agents ; isolation & purification ; pharmacology ; Drug Evaluation, Preclinical ; methods ; Genes, Reporter ; HEK293 Cells ; Humans ; Influenzavirus A ; enzymology ; Luciferases ; genetics ; metabolism ; Oseltamivir ; pharmacology ; Plasmids ; RNA Replicase ; antagonists & inhibitors ; metabolism ; Reproducibility of Results ; Ribavirin ; pharmacology ; Sensitivity and Specificity ; Transfection ; Zanamivir ; pharmacology

More than 60 antiviral agents for various infectious diseases such as herpes, hepatitis, influenza, and AIDS are currently prescribed worldwide. Among the viral infections, hepatitis B and influenza are those frequently seen in primary care situations in Korea. This review discusses the anti-hepatitis B (HBV) drugs entecavir and adefovir, and the anti-influenza drugs oseltamivir and zanamivir. In addition, the pharmacology and therapeutic guidance suggested by the Korean Association for the Study of the Liver were reviewed for entecavir and adepovir, the most frequently prescribed anti-HBV drugs. For influenza, oseltamivir is commonly used despite debates on neuropsychiatric safety issues and zanamivir may be used when an inhalation form is necessary. Although currently used drugs show considerable clinical efficacy, efforts to optimize their use and further research to find new molecules that may overcome their limitations are necessary.
Adenine ; Antiviral Agents ; Communicable Diseases ; Guanine ; Hepatitis ; Hepatitis B ; Influenza, Human ; Inhalation ; Korea ; Liver ; Organophosphonates ; Oseltamivir ; Primary Health Care ; Zanamivir

It has been suggested that oseltamivir-resistant influenza viruses harboring the H274/275Y mutation are less virulent than are those that are oseltamivir-sensitive, and fatality attributed to infection with an oseltamivir-resistant virus is very rare. Here we report the first fatal adult case of oseltamivir-resistant 2009 pandemic influenza A (H1N1) in Korea. A 60-year-old Korean male who had hypertension, diabetes mellitus, chronic kidney disease, and dilated cardiomyopathy visited Chonnam National University Hospital because of a 7-day history of chest pain and dyspnea. The patient was at another clinic and had been medicated with oseltamivir (75 mg twice daily) beginning 7 days before admission. Empirical antibiotics were started on the first day of hospitalization. Reverse-transcriptase polymerase chain reaction for 2009 pandemic influenza A (H1N1) was reported to be positive, and a double dose of oseltamivir (150 mg twice per day) was started on day four of hospitalization. However, the pneumonia worsened and the patient died, despite 3 days of high-dose antiviral therapy and 6 days of antibacterial therapy. An H275Y mutation was detected in the neuraminidase gene sequence. This case shows that oseltamivir resistance after short-term drug exposure is possible and can be fatal, emphasizing that early use of zanamivir should be considered in suspicious cases.
Adult ; Anti-Bacterial Agents ; Cardiomyopathy, Dilated ; Chest Pain ; Diabetes Mellitus ; Drug Resistance, Viral ; Dyspnea ; Hospitalization ; Humans ; Hypertension ; Influenza A Virus, H1N1 Subtype ; Influenza, Human ; Korea ; Male ; Middle Aged ; Neuraminidase ; Orthomyxoviridae ; Oseltamivir ; Pandemics ; Pneumonia ; Polymerase Chain Reaction ; Renal Insufficiency, Chronic ; Viruses ; Zanamivir