ABSTRACT
Rhinoviruses (RVs) cause the common cold and are associated with exacerbations of chronic inflammatory respiratory diseases, especially asthma and chronic obstructive pulmonary disease (COPD). We have assessed the antiviral drugs Anaferon for Children (AC) and Ergoferon (containing AC as one of the active pharmaceutical ingredients) in in vitro and in vivo experimental models, in order to evaluate their anti-rhinoviral and immunomodulatory potential. HeLa cells were pretreated with AC, and levels of the interferon-stimulated gene (ISG), 2'-5'-oligoadenylate synthetase 1 (OAS1-A) and viral replication were analyzed. In a mouse model of RV-induced exacerbation of allergic airway inflammation we administered Ergoferon and analyzed its effect on type I (IFN-ß), type II (IFN-γ) and type III (IFN-λ) IFNs induction, cell counts in bronchoalveolar lavage (BAL), cytokine (interleukin (IL)-4; IL-6) and chemokine (CXCL10/IP-10; CXCL1/KC) levels. It was shown that AC increased OAS1-Ð production and significantly decreased viral replication in vitro. Increased IFNs expression together with reduced neutrophils/lymphocytes recruitment and correlated IL-4/IL-6 declination was demonstrated for Ergoferon in vivo. However, there was no effect on examined chemokines. We conclude that AC and Ergoferon possess effects against RV infection and may have potential as novel therapies against RV-induced exacerbations of asthma.
Subject(s)
Antibodies/pharmacology , Antiviral Agents/immunology , Antiviral Agents/pharmacology , Picornaviridae Infections/drug therapy , Rhinovirus/drug effects , 2',5'-Oligoadenylate Synthetase/analysis , Animals , Asthma/immunology , Asthma/virology , Cell Line , Chemokines/metabolism , Child , Cytokines/drug effects , Cytokines/metabolism , Disease Models, Animal , Gene Expression/drug effects , HeLa Cells , Humans , Inflammation , Interferons/drug effects , Mice , Mice, Inbred BALB C , Respiratory System/immunology , Respiratory System/virology , Rhinovirus/pathogenicityABSTRACT
BACKGROUND: The influenza A virus accounts for serious annual viral upper respiratory tract infections. It is constantly able to modify its antigenic structure, thus evading host defence mechanisms. Moreover, currently available anti-influenza agents have a rather limited application, emphasizing the further need for new effective treatments. One of them is ergoferon, a drug containing combined polyclonal antibodies - anti-interferon gamma, anti-CD4 receptor and anti-histamine - in released-active form. The purpose of the study was to assess ergoferon antiviral efficacy in mice challenged with the A/Aichi/2/68 (H3N2) influenza virus. METHODS: The virus was inoculated intranasally at a 90% lethal dose. Ergoferon was administered at 0.4 ml/day per os in a preventive and therapeutic regimen - daily for 5 days prior to and for 16 days after the challenge. The reference product, Tamiflu (oseltamivir), was used as a positive control treatment - at 20 mg/kg/day for 5 days after the challenge. Mice in the negative control group received distilled water which had been utilized for test sample preparation; untreated control animals received no treatment. Antiviral efficacy was assessed by an increase in survival rate, average life expectancy and virus titre reduction in the challenged mouse lungs. RESULTS: Survival rate and average life expectancy values were increased significantly in groups treated with ergoferon and Tamiflu, as compared with controls. Lung virus titres were reduced in these groups as observed on days 2 and 4 post-inoculation. CONCLUSIONS: Ergoferon demonstrated antiviral activity by reducing the severity and duration of the major signs of induced influenza infection.
Subject(s)
Antibodies/pharmacology , Antiviral Agents/pharmacology , Immunologic Factors/pharmacology , Influenza A Virus, H3N2 Subtype/drug effects , Orthomyxoviridae Infections/drug therapy , Animals , CD4 Antigens/antagonists & inhibitors , CD4 Antigens/immunology , Drug Administration Schedule , Drug Dosage Calculations , Female , Histamine/immunology , Influenza A Virus, H3N2 Subtype/growth & development , Influenza A Virus, H3N2 Subtype/immunology , Interferon-gamma/antagonists & inhibitors , Interferon-gamma/immunology , Longevity/immunology , Lung/drug effects , Lung/immunology , Lung/virology , Mice , Mice, Inbred BALB C , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/mortality , Orthomyxoviridae Infections/virology , Oseltamivir/pharmacology , Survival Analysis , Treatment Outcome , Viral Load/drug effectsABSTRACT
The assessment of dose-response is an essential part of drug development in terms of the determination of a drug's effective dose, finding the safety endpoint, estimation of the pharmacokinetic profile, and even validation of drug activity, especially for therapeutic agents with a principally novel mechanism of action. Drugs based on released-active forms of antibodies are a good example of such a target. In this study, the efficacy of the antiviral drug Anaferon for children (released-active form of antibodies to interferon-gamma) was tested in a dose-dependent manner (at doses of 0.13, 0.2, 0.4, 0.8 ml/mouse/day) in a murine model of acute pneumonia induced by influenza virus pandemic strain A/California/07/09 (H1N1). Administration of the drug at the two highest doses led to: a reduction in the virus infectious titer in lung tissue up to 4.2 lgEID50/20 mg of tissue; infected animals' life prolongation up to 6.7 days; an increase in the survival rate of up to 40% and a decrease in morphological signs of inflammation when compared to the control animals. In this study, the dose-response effect of Anaferon for Children was demonstrated on mice for the first time. This finding is especially important for drugs with a principally novel mechanism of action like drugs based on released-active forms of antibodies. J. Med. Virol. 89:759-766, 2017. © 2016 Wiley Periodicals, Inc.
Subject(s)
Antibodies/administration & dosage , Immunologic Factors/administration & dosage , Influenza A Virus, H1N1 Subtype/immunology , Orthomyxoviridae Infections/drug therapy , Pneumonia, Viral/drug therapy , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Lung/pathology , Lung/virology , Mice, Inbred BALB C , Survival Analysis , Treatment Outcome , Viral LoadABSTRACT
This text is aimed to provide the readers with detailed information about phenomenon of released-activity and reply on the specific risen questions.
