Antiviral drugs on influenza are important in the control program of influenza. Options for influenza treatment are currently limited to using the neuraminidase inhibitors (NAIs). Given limited effectiveness of NAIs and related resistance, there remains an urgent need for the development of influenza antiviral drugs that can improve the efficacy and provide low propensity of viral resistance. Several influenza-related antiviral drugs that are currently under the late-stage clinical trials all appear differently in the mechanism of action. It is hoped that when new antiviral drugs are licensed, care and outcomes of severe influenza cases will be improved.
Antiviral Agents/therapeutic use* ; Drug Resistance, Viral ; Enzyme Inhibitors/therapeutic use* ; Humans ; Influenza, Human/drug therapy* ; Neuraminidase/therapeutic use*

Influenza is a global contagious disease, which causes hundreds of thousands of people deaths. And new subtype of influenza may cause pandemic influenza, and lead to more serious consequence. Drugs for anti-influenza have played very important roles in influenza treatment and prevention, especially neuraminidase inhibitors are effective on both influenza A and B which have more safety and tolerance, therefore they have been widely used for influenza treatment. However, several viral drug-resistant cases have been reported. In this paper, the clinic therapy, prevention and drug resistance of neuraminidase inhibitors, including zanamivir, oseltamivir and peramivir, and progress in the research and development in our country are presented in order to promote research and development of new drugs for influenza treatment and prevention.
Antiviral Agents ; pharmacology ; therapeutic use ; Drug Resistance, Viral ; drug effects ; Enzyme Inhibitors ; pharmacology ; therapeutic use ; Humans ; Influenza, Human ; drug therapy ; prevention & control ; virology ; Neuraminidase ; antagonists & inhibitors ; Oseltamivir ; pharmacology ; therapeutic use ; Zanamivir ; pharmacology ; therapeutic use

OBJECTIVETo evaluate the efficacy and safety of oseltamivir phosphate as treatment for naturally acquired influenza infection.

METHODSThis study was conducted as a double-blind, randomized, placebo-controlled, multicenter trial during the influenza epidemic season from January to April 2001 at 7 centers in China. A total of 478 adults without other medical history, aged 18 to 65 years, were enrolled into the study. All subjects demonstrated febrile respiratory illness of no more than 36 hours' duration with a temperature of 37.8 degrees C or more plus at least two of the following symptoms: coryza/nasal congestion, sore throat, cough, myalgia/muscles aches and pain, fatigue, headache or chills/sweats. Individuals were randomized into either the oseltamivir phosphate or placebo group with identical-looking capsules. Either oral oseltamivir phosphate, 75 mg twice daily, or placebo was administered to the subjects for 5 days.

RESULTSA total of 451 individuals were analyzed for efficacy as the intent-to-treat population (ITT) (216 oseltamivir and 235 placebo) and 273 individuals were identified as influenza-infected through laboratory test, who were then defined as the intent-to-treat infected population (ITTI) (134 oseltamivir and 139 placebo). Four hundred and fifty nine individuals were included in the safety analysis. In the ITTI population, the cumulative alleviation proportion of oseltamivir group was significantly higher than that of the placebo group (P = 0.0466)). The median duration of illness was 91.6 h [95% confidence interval (CI) = 80.2 - 101.3 h] in the oseltamivir group and 95 h (95% CI = 84.5 - 105.3 h) in the placebo group. The median area under the curve of decreased total score was significantly higher in the oseltamivir group than in the placebo group, 1382.9 and 1236.7 score-hours, respectively (P = 0.0196). For the ITT population, similar results were observed. Adverse events (AE) were similarly reported in both the oseltamivir group and the placebo group. The main adverse events following test drug were gastrointestinal symptoms, neurological symptoms and rashes.

CONCLUSIONOseltamivir was effective and well tolerated as treatment of early naturally acquired influenza.

Acetamides ; adverse effects ; therapeutic use ; Adult ; Aged ; Antiviral Agents ; therapeutic use ; Double-Blind Method ; Enzyme Inhibitors ; therapeutic use ; Female ; Humans ; Influenza, Human ; drug therapy ; Male ; Middle Aged ; Neuraminidase ; antagonists & inhibitors ; Oseltamivir

Influenza is a major threat to millions of people worldwide. Vaccines and antiviral agents are two main options available to reduce the impact of the influenza virus, while anti-influenza agents are the most effective means to prevent the transmission of the highly contagious virus and to treat the epidemics of disease. At present, four anti-influenza agents have been approved by the FDA for the treatment of influenza, including two M2 protein ion channel inhibitors-amantadine and rimantadine and two neuraminidase inhibitors-zanamivir and oseltamivir. Arbidol hydrochloride, launched in Russia, is a potent inhibitor of influenza virus, too. Neuraminidase inhibitors could be classified generally by structure into six different kinds: sialic acid derivatives, benzoic acid derivatives, cyclohexene derivatives, cyclopentane derivatives, pyrrolidine derivatives and natural products. In this paper, recent progress in the research of the action mechanisms and structure-activity relationships of these anti-influenza virus agents were reviewed.
Amantadine ; chemical synthesis ; chemistry ; pharmacology ; therapeutic use ; Antiviral Agents ; chemical synthesis ; chemistry ; pharmacology ; therapeutic use ; Cyclopentanes ; chemical synthesis ; chemistry ; pharmacology ; therapeutic use ; Guanidines ; chemical synthesis ; chemistry ; pharmacology ; therapeutic use ; Humans ; Indoles ; chemical synthesis ; chemistry ; pharmacology ; therapeutic use ; Influenza, Human ; drug therapy ; Neuraminidase ; antagonists & inhibitors ; chemical synthesis ; chemistry ; pharmacology ; therapeutic use ; Orthomyxoviridae ; drug effects ; Oseltamivir ; chemical synthesis ; chemistry ; pharmacology ; therapeutic use ; Pyrrolidines ; chemical synthesis ; chemistry ; pharmacology ; therapeutic use ; Rimantadine ; chemical synthesis ; chemistry ; pharmacology ; therapeutic use ; Structure-Activity Relationship ; Viral Matrix Proteins ; antagonists & inhibitors ; chemical synthesis ; chemistry ; pharmacology ; therapeutic use ; Zanamivir ; chemical synthesis ; chemistry ; pharmacology ; therapeutic use

Animals ; Antiviral Agents ; pharmacology ; therapeutic use ; DNA-Directed RNA Polymerases ; antagonists & inhibitors ; Drug Discovery ; Hemagglutinin Glycoproteins, Influenza Virus ; chemistry ; metabolism ; Humans ; Influenza A virus ; drug effects ; genetics ; metabolism ; Influenza, Human ; drug therapy ; Molecular Targeted Therapy ; Neuraminidase ; antagonists & inhibitors ; RNA-Binding Proteins ; antagonists & inhibitors ; Signal Transduction ; drug effects ; Viral Core Proteins ; antagonists & inhibitors ; Viral Matrix Proteins ; antagonists & inhibitors

The use of antiviral drugs such as influenza neuraminidase (NA) inhibitors is a critical strategy to prevent and control flu pandemic, but this strategy faces the challenge of emerging drug-resistant strains. For a highly pathogenic avian influenza (HPAI) H5N1 virus, biosafety restrictions have significantly limited the efforts to monitor its drug responses and mechanisms involved. In this study, a rapid and biosafe assay based on NA pseudovirus was developed to study the resistance of HPAI H5N1 virus to NA inhibitor drugs. The H5N1 NA pseudovirus was comprehensively tested using oseltamivir-sensitive strains and their resistant mutants. Results were consistent with those in previous studies, in which live H5N1 viruses were used. Several oseltamivir-resistant mutations reported in human H1N1 were also identified to cause decreased oseltamivir sensitivity in H5N1 NA by using the H5N1 NA pseudovirus. Thus, H5N1 NA pseudoviruses could be used to monitor HPAI H5N1 drug resistance rapidly and safely.
Animals ; Birds ; Drug Resistance, Viral ; genetics ; Enzyme Inhibitors ; therapeutic use ; HEK293 Cells ; Humans ; Influenza A Virus, H1N1 Subtype ; drug effects ; genetics ; pathogenicity ; Influenza A Virus, H5N1 Subtype ; drug effects ; genetics ; pathogenicity ; Influenza in Birds ; drug therapy ; genetics ; virology ; Influenza, Human ; drug therapy ; genetics ; virology ; Mutagenesis, Site-Directed ; Neuraminidase ; antagonists & inhibitors ; genetics ; Oseltamivir ; administration & dosage

OBJECTIVETo explore the potential effects of berberine on influenza virus infection both in vitro and in vivo.

METHODSIn vitro anti-influenza virus assays were performed by cytopathogenic effect and neuraminidase assays in Madin Darby canine kidney cells. In vivo anti-influenza virus assays were performed on the viral pneumonia model of mice. The numbers of mice that died within day 2 to day 14 postinfection were recorded to calculate the mortality. On days 2, 4, and 6, the viral titers in the lungs were determined by hemagglutination assay; hematoxylin/eosin staining was used to assess the pathogenic changes of lung tissues; the concentrations of tumor necrosis factor-alpha (TNF-α) and monocyte specific chemoattractant molecule (MCP-1) were measured by radio immunoassay or enzyme-linked immunosorbent assay; the concentrations of nitric oxide (NO) and inducible nitric oxide synthetase (iNOS) were detected by colorimetric method; reverse transcription polymerase chain reaction was used to detect the mRNA level of TNF-α and MCP-1.

RESULTSBerberine showed inhibitory effects on cytopathogenic effects and neuraminidase activity of virus, with the therapeutic index 9.69. In vivo, berberine decreased mice mortality from 90% to 55%, reduced virus titers in the lungs on day 2 postinfection (P<0.05). The lung histology scores were 1.50 ± 0.67, 4.50 ± 1.00, and 5.50 ± 1.00 in the berberine group on days 2, 4, and 6, respectively, which were significantly reduced compared to 2.17 ± 0.22, 6.83 ± 0.44, and 8.50 ± 0.33 in the infected group (P<0.05). The productions of NO and iNOS were repressed by berberine compared with those in the infected group (P<0.01). The transcription and expression of TNF-α were inhibited by berberine on day 4 (P<0.01) and day 6 (P<0.05), and those of MCP-1 were inhibited on day 6 (P<0.01) compared with the infected group.

CONCLUSIONSBerberine exhibited antiviral effects on the influenza virus both in vitro and in vivo. The possible therapeutic mechanism of berberine on influenza-induced viral pneumonia might be inhibiting the virus infection, as well as improving the pathogenic changes by repressing inflammatory substances release.

Animals ; Antiviral Agents ; pharmacology ; therapeutic use ; Berberine ; pharmacology ; therapeutic use ; Cell Line ; Chemokine CCL2 ; genetics ; metabolism ; Dogs ; Female ; Lung ; drug effects ; enzymology ; pathology ; virology ; Male ; Mice ; Neuraminidase ; metabolism ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase Type II ; metabolism ; Orthomyxoviridae ; drug effects ; enzymology ; Orthomyxoviridae Infections ; complications ; drug therapy ; pathology ; virology ; Pneumonia ; complications ; drug therapy ; pathology ; virology ; Reactive Oxygen Species ; metabolism ; Survival Analysis ; Transcription, Genetic ; drug effects ; Tumor Necrosis Factor-alpha ; genetics ; metabolism