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Sample records for antiviral drug oseltamivir

  1. Detection of the antiviral drug oseltamivir in aquatic environments.

    Directory of Open Access Journals (Sweden)

    Hanna Söderström

    Full Text Available Oseltamivir (Tamiflu is the most important antiviral drug available and a cornerstone in the defence against a future influenza pandemic. Recent publications have shown that the active metabolite, oseltamivir carboxylate (OC, is not degraded in sewage treatment plants and is also persistent in aquatic environments. This implies that OC will be present in aquatic environments in areas where oseltamivir is prescribed to patients for therapeutic use. The country where oseltamivir is used most is Japan, where it is used to treat seasonal flu. We measured the levels of OC in water samples from the Yodo River system in the Kyoto and Osaka prefectures, Japan, taken before and during the flu-season 2007/8. No OC was detected before the flu-season but 2-58 ng L(-1 was detected in the samples taken during the flu season. This study shows, for the first time, that low levels of oseltamivir can be found in the aquatic environment. Therefore the natural reservoir of influenza virus, dabbling ducks, is exposed to oseltamivir, which could promote the evolution of viral resistance.

  2. Adsorption removal of antiviral drug oseltamivir and its metabolite oseltamivir carboxylate by carbon nanotubes: Effects of carbon nanotube properties and media.

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    Wang, Wen-Long; Wu, Qian-Yuan; Wang, Zheng-Ming; Niu, Li-Xia; Wang, Chao; Sun, Ming-Chao; Hu, Hong-Ying

    2015-10-01

    This investigation evaluated the adsorption behavior of the antiviral drugs of oseltamivir (OE) and its metabolites (i.e., oseltamivir carboxylate (OC)) on three types of carbon nanotubes (CNTs) including single-walled CNT (SWCNT), multi-walled CNT (MWCNT), and carboxylated SWCNT (SWCNT-COOH). CNTs can efficiently remove more than 90% of the OE and OC from aqueous solution when the initial concentration was lower than 10(-4) mmol/L. The Polanyi-Manes model depicted the adsorption isotherms of OE and OC on CNTs better than the Langmuir and Freundlich models. The properties of OE/OC and the characteristics of CNTs, particularly the oxygen functional groups (e.g., SWCNT-COOH) played important roles during the adsorption processes. OE showed a higher adsorption affinity than OC. By comparing the different adsorbates adsorption on each CNT and each adsorbate adsorption on different CNTs, the adsorption mechanisms of hydrophobic interaction, electrostatic interaction, van der Waals force, and H-bonding were proposed as the contributing factors for OE and OC adsorption on CNTs. Particularly, for verifying the contribution of electrostatic interaction, the changes of adsorption partition efficiency (Kd) of OE and OC on CNTs were evaluated by varying pH from 2 to 11 and the importance of isoelectric point (pHIEP) of CNTs on OE and OC adsorption was addressed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. 75 FR 20429 - Amended Authorizations of Emergency Use of Certain Antiviral Drugs Zanamivir and Oseltamivir...

    Science.gov (United States)

    2010-04-19

    ... Zanamivir Summary Fact Sheet for Patients and Parents were attached to the letter. \\2\\ FDA is authorizing... Authorization letters for certain zanamivir and oseltamivir phosphate products. Finally, on November 4, 2009, FDA amended and reissued in its entirety the Authorization letter for certain zanamivir inhalation...

  4. Oseltamivir

    Directory of Open Access Journals (Sweden)

    Tullu M

    2009-01-01

    Full Text Available Oseltamivir, a selective neuraminidase enzyme inhibitor, has gained worldwide attention in view of Influenza A (H1N1 pandemic. It is one of the most important drugs effective against the novel influenza virus. Oseltamivir is used for the treatment of uncomplicated acute illness due to influenza infection. Early initiation of treatment with the drug provides greater clinical benefits. The drug can also be effectively used for prophylaxis. Oseltamivir is readily absorbed from the gastrointestinal tract and is converted to the active metabolite- oseltamivir carboxylate, which has a wider distribution in the body. Oseltamivir carboxylate is eliminated in the urine with a half-life of 6-10 h. The drug is generally well-tolerated and does not have many clinically significant drug interactions. Nausea and vomiting are the commonest adverse effects associated with its use. The standard adult dose for treatment is 75 mg twice a day for five days and the dose for prophylaxis is 75 mg once daily for at least seven days following contact with an infected individual. The dose needs to be adjusted in patients with renal failure but no adjustments are required in patients with hepatic impairment. Although most of the influenza virus strains are sensitive to oseltamivir, development of drug resistance may limit the clinical utility of the drug in the future.

  5. Removal of the antiviral agent oseltamivir and its biological activity by oxidative processes

    International Nuclear Information System (INIS)

    Mestankova, Hana; Schirmer, Kristin; Escher, Beate I.; Gunten, Urs von

    2012-01-01

    The antiviral agent oseltamivir acid (OA, the active metabolite of Tamiflu ® ) may occur at high concentrations in wastewater during pandemic influenza events. To eliminate OA and its antiviral activity from wastewater, ozonation and advanced oxidation processes were investigated. For circumneutral pH, kinetic measurements yielded second-order rate constants of 1.7 ± 0.1 × 10 5 and 4.7 ± 0.2 × 10 9 M −1 s −1 for the reaction of OA with ozone and hydroxyl radical, respectively. During the degradation of OA by both oxidants, the antiviral activity of the treated aqueous solutions was measured by inhibition of neuraminidase activity of two different viral strains. A transient, moderate (two-fold) increase in antiviral activity was observed in solutions treated up to a level of 50% OA transformation, while for higher degrees of transformation the activity corresponded to that caused exclusively by OA. OA was efficiently removed by ozonation in a wastewater treatment plant effluent, suggesting that ozonation can be applied to remove OA from wastewater. - Highlights: ► Oseltamivir acid (OA) is oxidized by ozone and hydroxyl radical. ► Kinetics: We determined rate constants for the reaction with these oxidants. ► The specific activity of OA as neuraminidase inhibitor disappeared during oxidation. ► Ozonation and advanced oxidation can effectively remove OA from wastewaters. - Ozone and hydroxyl radical treatment processes can degrade aqueous oseltamivir acid and remove its antiviral activity.

  6. Oseltamivir, amantadine, and ribavirin combination antiviral therapy versus oseltamivir monotherapy for the treatment of influenza: a multicentre, double-blind, randomised phase 2 trial.

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    Beigel, John H; Bao, Yajing; Beeler, Joy; Manosuthi, Weerawat; Slandzicki, Alex; Dar, Sadia M; Panuto, John; Beasley, Richard L; Perez-Patrigeon, Santiago; Suwanpimolkul, Gompol; Losso, Marcelo H; McClure, Natalie; Bozzolo, Dawn R; Myers, Christopher; Holley, H Preston; Hoopes, Justin; Lane, H Clifford; Hughes, Michael D; Davey, Richard T

    2017-12-01

    Influenza continues to have a substantial socioeconomic and health impact despite a long established vaccination programme and approved antivirals. Preclinical data suggest that combining antivirals might be more effective than administering oseltamivir alone in the treatment of influenza. We did a randomised, double-blind, multicentre phase 2 trial of a combination of oseltamivir, amantadine, and ribavirin versus oseltamivir monotherapy with matching placebo for the treatment of influenza in 50 sites, consisting of academic medical centre clinics, emergency rooms, and private physician offices in the USA, Thailand, Mexico, Argentina, and Australia. Participants who were aged at least 18 years with influenza and were at increased risk of complications were randomly assigned (1:1) by an online computer-generated randomisation system to receive either oseltamivir (75 mg), amantadine (100 mg), and ribavirin (600 mg) combination therapy or oseltamivir monotherapy twice daily for 5 days, given orally, and participants were followed up for 28 days. Blinded treatment kits were used to achieve masking of patients and staff. The primary endpoint was the percentage of participants with virus detectable by PCR in nasopharyngeal swab at day 3, and was assessed in participants who were randomised, had influenza infection confirmed by the central laboratory on a baseline nasopharyngeal sample, and had received at least one dose of study drug. Safety assessment was done in all patients in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01227967. Between March 1, 2011, and April 29, 2016, 633 participants were randomly assigned to receive combination antiviral therapy (n=316) or monotherapy (n=317). Seven participants were excluded from analysis: three were not properly randomised, three withdrew from the study, and one was lost to follow-up. The primary analysis included 394 participants, excluding 47 in the pilot phase, 172 without

  7. Interdisciplinary pharmacometrics linking oseltamivir pharmacology, influenza epidemiology and health economics to inform antiviral use in pandemics.

    Science.gov (United States)

    Kamal, Mohamed A; Smith, Patrick F; Chaiyakunapruk, Nathorn; Wu, David B C; Pratoomsoot, Chayanin; Lee, Kenneth K C; Chong, Huey Yi; Nelson, Richard E; Nieforth, Keith; Dall, Georgina; Toovey, Stephen; Kong, David C M; Kamauu, Aaron; Kirkpatrick, Carl M; Rayner, Craig R

    2017-07-01

    A modular interdisciplinary platform was developed to investigate the economic impact of oseltamivir treatment by dosage regimen under simulated influenza pandemic scenarios. The pharmacology module consisted of a pharmacokinetic distribution of oseltamivir carboxylate daily area under the concentration-time curve at steady state (simulated for 75 mg and 150 mg twice daily regimens for 5 days) and a pharmacodynamic distribution of viral shedding duration obtained from phase II influenza inoculation data. The epidemiological module comprised a susceptible, exposed, infected, recovered (SEIR) model to which drug effect on the basic reproductive number (R 0 ), a measure of transmissibility, was linked by reduction of viral shedding duration. The number of infected patients per population of 100 000 susceptible individuals was simulated for a series of pandemic scenarios, varying oseltamivir dose, R 0 (1.9 vs. 2.7), and drug uptake (25%, 50%, and 80%). The number of infected patients for each scenario was entered into the health economics module, a decision analytic model populated with branch probabilities, disease utility, costs of hospitalized patients developing complications, and case-fatality rates. Change in quality-adjusted life years was determined relative to base case. Oseltamivir 75 mg relative to no treatment reduced the median number of infected patients, increased change in quality-adjusted life years by deaths averted, and was cost-saving under all scenarios; 150 mg relative to 75 mg was not cost effective in low transmissibility scenarios but was cost saving in high transmissibility scenarios. This methodological study demonstrates proof of concept that the disciplines of pharmacology, disease epidemiology and health economics can be linked in a single quantitative framework. © 2017 The British Pharmacological Society.

  8. Antiviral Drugs: Seasonal Flu

    Centers for Disease Control (CDC) Podcasts

    2010-09-29

    In this podcast, Dr. Joe Bresee explains the nature of antiviral drugs and how they are used for seasonal flu.  Created: 9/29/2010 by National Center for Immunization and Respiratory Diseases (NCIRD).   Date Released: 9/29/2010.

  9. Application of electrolysis for inactivation of an antiviral drug that is one of possible selection pressure to drug-resistant influenza viruses.

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    Kobayashi, Toyohide; Hirose, Jun; Wu, Hong; Sano, Kouichi; Katsumata, Takahiro; Tsujibo, Hiroshi; Nakano, Takashi

    2013-12-01

    The recent development of antiviral drugs has led to concern that the release of the chemicals in surface water due to expanded medical use could induce drug-resistant mutant viruses in zoonosis. Many researchers have noted that the appearance of an oseltamivir (Tamiflu(®))-resistant avian influenza mutant virus, which may spread to humans, could be induced by oseltamivir contamination of surface water. Although past studies have reported electrolysis as a possible method for degradation of antineoplastics and antibacterials in water, the validity of the method for treatment of antiviral drugs is unknown. In this study, electrolysis was used to degrade an antiviral prodrug, oseltamivir, and a stable active form, oseltamivir carboxylate, and the degradation process was monitored with HPLC-UV and the neuraminidase inhibitory assay. HPLC-UV-detectable oseltamivir and oseltamivir carboxylate were decomposed by electrolysis within 60 min, and inhibitory activity of neuraminidase decreased below the detection limit of the assay used. Cytotoxic and genotoxic activity were not detected in electrolyzed fluid. These results indicate that electrolysis is a possible treatment for inactivation of the antiviral drug oseltamivir. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Environmental levels of the antiviral oseltamivir induce development of resistance mutation H274Y in influenza A/H1N1 virus in mallards.

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    Josef D Järhult

    Full Text Available Oseltamivir (Tamiflu® is the most widely used drug against influenza infections and is extensively stockpiled worldwide as part of pandemic preparedness plans. However, resistance is a growing problem and in 2008-2009, seasonal human influenza A/H1N1 virus strains in most parts of the world carried the mutation H274Y in the neuraminidase gene which causes resistance to the drug. The active metabolite of oseltamivir, oseltamivir carboxylate (OC, is poorly degraded in sewage treatment plants and surface water and has been detected in aquatic environments where the natural influenza reservoir, dabbling ducks, can be exposed to the substance. To assess if resistance can develop under these circumstances, we infected mallards with influenza A/H1N1 virus and exposed the birds to 80 ng/L, 1 µg/L and 80 µg/L of OC through their sole water source. By sequencing the neuraminidase gene from fecal samples, we found that H274Y occurred at 1 µg/L of OC and rapidly dominated the viral population at 80 µg/L. IC₅₀ for OC was increased from 2-4 nM in wild-type viruses to 400-700 nM in H274Y mutants as measured by a neuraminidase inhibition assay. This is consistent with the decrease in sensitivity to OC that has been noted among human clinical isolates carrying H274Y. Environmental OC levels have been measured to 58-293 ng/L during seasonal outbreaks and are expected to reach µg/L-levels during pandemics. Thus, resistance could be induced in influenza viruses circulating among wild ducks. As influenza viruses can cross species barriers, oseltamivir resistance could spread to human-adapted strains with pandemic potential disabling oseltamivir, a cornerstone in pandemic preparedness planning. We propose surveillance in wild birds as a measure to understand the resistance situation in nature and to monitor it over time. Strategies to lower environmental levels of OC include improved sewage treatment and, more importantly, a prudent use of antivirals.

  11. Treatment of Oseltamivir-Resistant Influenza A (H1N1) Virus Infections in Mice With Antiviral Agents

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    Smee, Donald F.; Julander, Justin G.; Tarbet, E. Bart; Gross, Matthew; Nguyen, Jack

    2012-01-01

    Influenza A/Mississippi/03/2001 (H1N1) and A/Hong Kong/2369/2009 (H1N1) viruses containing the neuraminidase gene mutation H275Y (conferring resistance to oseltamivir) were adapted to mice and evaluated for suitability as models for lethal infection and antiviral treatment. The viral neuraminidases were resistant to peramivir and oseltamivir carboxylate but sensitive to zanamivir. Similar pattern of antiviral activity were seen in MDCK cell assays. Lethal infections were achieved in mice with the two viruses. Oral oseltamivir at 100 and 300 mg/kg/day bid for 5 d starting at −2 h gave 30 and 60% protection from death, respectively, due to the A/Mississippi/03/2001 infection. Intraperitoneal treatments with zanamivir at 30 and 100 mg/kg/day starting at −2 h gave 60 and 90% protection, respectively. Neither compound at ≤300 mg/kg/day protected mice when treatments began at +24 h. Amantadine was effective at 10, 30, and 100 mg/kg/day, rimantadine was protective at 10 and 30 mg/kg/day (highest dose tested), and ribavirin was active at 30 and 75 mg/kg/day, with survival ranging from 60–100% for oral treatments initiated at −2 h. For treatments begun at +24 h, amantadine was protective at 30 and 100 mg/kg/day, rimantadine showed efficacy at 10 and 30 mg/kg/day, and ribavirin was active at 75 mg/kg/day, with 60–100% survival per group. In the A/Hong Kong/2369/2009 infection, oral oseltamivir at 100 and 300 mg/kg/day starting at −2 h gave 50 and 70% protection from death, respectively. These infection models will be useful to study newly discovered anti-influenza virus agents and to evaluate compounds in combination. PMID:22809862

  12. Oseltamivir prescription and regulatory actions vis-à-vis abnormal behavior risk in Japan: drug utilization study using a nationwide pharmacy database.

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    Urushihara, Hisashi; Doi, Yuko; Arai, Masaru; Matsunaga, Toshiyuki; Fujii, Yosuke; Iino, Naoko; Kawamura, Takashi; Kawakami, Koji

    2011-01-01

    In March 2007, a regulatory advisory was issued in Japan to restrict oseltamivir use in children aged 10-19 years because of safety concerns over abnormal behavior. The effectiveness and validity of regulatory risk minimization actions remain to be reviewed, despite their significant public health implications. To assess the impact of the regulatory actions on prescribing practices and safety reporting. METHODOLOY/PRINICPAL FINDINGS: In this retrospective review of a nationwide pharmacy database, we analyzed 100,344 dispensation records for oseltamivir and zanamivir for the period from November 2006 to March 2009. The time trend in dispensations for these antiviral agents was presented before and after the regulatory actions, contrasted with intensity of media coverage and the numbers of spontaneous adverse reaction reports with regard to antivirals. The 2007 regulatory actions, together with its intense media coverage, reduced oseltamivir dispensation in targeted patients in fiscal year 2008 to 20.4% of that in fiscal year 2006, although influenza activities were comparable between these fiscal years. In contrast, zanamivir dispensation increased approximately nine-fold across all age groups. The number of abnormal behavior reports associated with oseltamivir in children aged 10-19 years decreased from fiscal year 2006 to 2008 (24 to 9 cases); this decline was offset by the increased number of reports of abnormal behavior in children under age 10 (12 to 28 cases). The number of reports associated with zanamivir increased in proportion to increased dispensation of this drug (11 to 114 cases). The 2007 actions effectively reduced oseltamivir prescriptions and the number of reports of abnormal behavior in the targeted group. The observed increase in abnormal behavior reports in oseltamivir patients under age 10 and in zanamivir patients suggests that these patient groups may also be at risk, calling into question the validity of the current discrimination by age and

  13. Oseltamivir prescription and regulatory actions vis-à-vis abnormal behavior risk in Japan: drug utilization study using a nationwide pharmacy database.

    Directory of Open Access Journals (Sweden)

    Hisashi Urushihara

    Full Text Available BACKGROUND: In March 2007, a regulatory advisory was issued in Japan to restrict oseltamivir use in children aged 10-19 years because of safety concerns over abnormal behavior. The effectiveness and validity of regulatory risk minimization actions remain to be reviewed, despite their significant public health implications. To assess the impact of the regulatory actions on prescribing practices and safety reporting. METHODOLOY/PRINICPAL FINDINGS: In this retrospective review of a nationwide pharmacy database, we analyzed 100,344 dispensation records for oseltamivir and zanamivir for the period from November 2006 to March 2009. The time trend in dispensations for these antiviral agents was presented before and after the regulatory actions, contrasted with intensity of media coverage and the numbers of spontaneous adverse reaction reports with regard to antivirals. The 2007 regulatory actions, together with its intense media coverage, reduced oseltamivir dispensation in targeted patients in fiscal year 2008 to 20.4% of that in fiscal year 2006, although influenza activities were comparable between these fiscal years. In contrast, zanamivir dispensation increased approximately nine-fold across all age groups. The number of abnormal behavior reports associated with oseltamivir in children aged 10-19 years decreased from fiscal year 2006 to 2008 (24 to 9 cases; this decline was offset by the increased number of reports of abnormal behavior in children under age 10 (12 to 28 cases. The number of reports associated with zanamivir increased in proportion to increased dispensation of this drug (11 to 114 cases. CONCLUSIONS/SIGNIFICANCE: The 2007 actions effectively reduced oseltamivir prescriptions and the number of reports of abnormal behavior in the targeted group. The observed increase in abnormal behavior reports in oseltamivir patients under age 10 and in zanamivir patients suggests that these patient groups may also be at risk, calling into question

  14. Smallpox Antiviral Drug

    Science.gov (United States)

    2007-01-01

    phogenic proteolysis is crucial for simple RNA viruses such as poliovirus and HIV, and also appears to play a central role in the assembly of more...al particles [14]; unidirectional packaging of bacteriophage T4 DNA [15]; completion of the infectious poliovirus virion in a flexible configuration...effects of an antiviral both in vitro and in vivo. Some viruses have not been adapted to grow in tissue culture cells or due to their genetic makeup are

  15. The Use of Antiviral Drugs for Influenza: Guidance for Practitioners 2012/2013

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    Fred Y Aoki

    2012-01-01

    Seasonal influenza in 2012/2013 is predicted to be caused by two human influenza A and one influenza B strain, all of which are anticipated to remain generally susceptible to oseltamivir.The predicted strains are A/California/7/2009 (H1N1 pdm09-like, A/Victoria/361/2011 (H3N2-like and B/Wisconsin/1/2010-like (Yamagata lineage. All are included in the seasonal influenza vaccine and are susceptible to oseltamivir.Swine-variant H3N2v, which has rarely caused infection in humans exposed to infected swine within the past year in the United States, is susceptible to oseltamivir. It is not included in the current seasonal influenza vaccine.It is still considered that initiation of antiviral therapy more than 36 h to 48 h after onset of symptoms is beneficial in patients hospitalized with complicated influenza and severe illness.Oseltamivir continues to be recommended for the treatment of influenza in pregnant women.The use of antiviral drugs among measures to control outbreaks of influenza in closed facilities such as correctional institutions is now included in the present document.

  16. Enabling the intestinal absorption of highly polar antiviral agents: ion-pair facilitated membrane permeation of zanamivir heptyl ester and guanidino oseltamivir.

    Science.gov (United States)

    Miller, Jonathan M; Dahan, Arik; Gupta, Deepak; Varghese, Sheeba; Amidon, Gordon L

    2010-08-02

    Antiviral drugs often suffer from poor intestinal permeability, preventing their delivery via the oral route. The goal of this work was to enhance the intestinal absorption of the low-permeability antiviral agents zanamivir heptyl ester (ZHE) and guanidino oseltamivir (GO) utilizing an ion-pairing approach, as a critical step toward making them oral drugs. The counterion 1-hydroxy-2-naphthoic acid (HNAP) was utilized to enhance the lipophilicity and permeability of the highly polar drugs. HNAP substantially increased the log P of the drugs by up to 3.7 log units. Binding constants (K(11(aq))) of 388 M(-1) for ZHE-HNAP and 2.91 M(-1) for GO-HNAP were obtained by applying a quasi-equilibrium transport model to double-reciprocal plots of apparent octanol-buffer distribution coefficients versus HNAP concentration. HNAP enhanced the apparent permeability (P(app)) of both compounds across Caco-2 cell monolayers in a concentration-dependent manner, as substantial P(app) (0.8-3.0 x 10(-6) cm/s) was observed in the presence of 6-24 mM HNAP, whereas no detectable transport was observed without counterion. Consistent with a quasi-equilibrium transport model, a linear relationship with slope near 1 was obtained from a log-log plot of Caco-2 P(app) versus HNAP concentration, supporting the ion-pair mechanism behind the permeability enhancement. In the rat jejunal perfusion assay, the addition of HNAP failed to increase the effective permeability (P(eff)) of GO. However, the rat jejunal permeability of ZHE was significantly enhanced by the addition of HNAP in a concentration-dependent manner, from essentially zero without HNAP to 4.0 x 10(-5) cm/s with 10 mM HNAP, matching the P(eff) of the high-permeability standard metoprolol. The success of ZHE-HNAP was explained by its >100-fold stronger K(11(aq)) versus GO-HNAP, making ZHE-HNAP less prone to dissociation and ion-exchange with competing endogenous anions and able to remain intact during membrane permeation. Overall, this

  17. Can antiviral drugs contain pandemic influenza transmission?

    Directory of Open Access Journals (Sweden)

    Niels G Becker

    Full Text Available Antiviral drugs dispensed during the 2009 influenza pandemic generally failed to contain transmission. This poses the question of whether preparedness for a future pandemic should include plans to use antiviral drugs to mitigate transmission.Simulations using a standard transmission model that allows for infected arrivals and delayed vaccination show that attempts to contain transmission require relatively few antiviral doses. In contrast, persistent use of antiviral drugs when the reproduction number remains above 1 use very many doses and are unlikely to reduce the eventual attack rate appreciably unless the stockpile is very large. A second model, in which the community has a household structure, shows that the effectiveness of a strategy of dispensing antiviral drugs to infected households decreases rapidly with time delays in dispensing the antivirals. Using characteristics of past pandemics it is estimated that at least 80% of primary household cases must present upon show of symptoms to have a chance of containing transmission by dispensing antiviral drugs to households. To determine data needs, household outbreaks were simulated with 50% receiving antiviral drugs early and 50% receiving antiviral drugs late. A test to compare the size of household outbreaks indicates that at least 100-200 household outbreaks need to be monitored to find evidence that antiviral drugs can mitigate transmission of the newly emerged virus.Use of antiviral drugs in an early attempt to contain transmission should be part of preparedness plans for a future influenza pandemic. Data on the incidence of the first 350 cases and the eventual attack rates of the first 200 hundred household outbreaks should be used to estimate the initial reproduction number R and the effectiveness of antiviral drugs to mitigate transmission. Use of antiviral drugs to mitigate general transmission should cease if these estimates indicate that containment of transmission is unlikely.

  18. Antiviral Resistance to Influenza Viruses: Clinical and Epidemiological Aspects

    NARCIS (Netherlands)

    van der Vries, E.

    2017-01-01

    There are three classes of antiviral drugs approved for the treatment of influenza: the M2 ion channel inhibitors (amantadine, rimantadine), neuraminidase (NA) inhibitors (laninamivir, oseltamivir, peramivir, zanamivir), and the protease inhibitor (favipiravir); some of the agents are only available

  19. New pathogenic viruses and novel antiviral drugs

    NARCIS (Netherlands)

    Berkhout, Ben; Eggink, Dirk

    2011-01-01

    The journal Antiviral Research was conceived and born in 1980, and launched in 1981, a time when very few antiviral drugs were around. This 30-year celebration meeting was convened by the publisher Elsevier and chaired by Eric de Clercq (Leuven University), who has acted as editor-in-chief for the

  20. Highlights in antiviral drug research: antivirals at the horizon.

    Science.gov (United States)

    De Clercq, Erik

    2013-11-01

    This review highlights ten "hot topics" in current antiviral research: (i) new nucleoside derivatives (i.e., PSI-352938) showing high potential as a direct antiviral against hepatitis C virus (HCV); (ii) cyclopropavir, which should be further pursued for treatment of human cytomegalovirus (HCMV) infections; (iii) North-methanocarbathymidine (N-MCT), with a N-locked conformation, showing promising activity against both α- and γ-herpesviruses; (iv) CMX001, an orally bioavailable prodrug of cidofovir with broad-spectrum activity against DNA viruses, including polyoma, adeno, herpes, and pox; (v) favipiravir, which is primarily pursued for the treatment of influenza virus infections, but also inhibits the replication of other RNA viruses, particularly (-)RNA viruses such as arena, bunya, and hanta; (vi) newly emerging antiarenaviral compounds which should be more effective (and less toxic) than the ubiquitously used ribavirin; (vii) antipicornavirus agents in clinical development (pleconaril, BTA-798, and V-073); (viii) natural products receiving increased attention as potential antiviral drugs; (ix) antivirals such as U0126 targeted at specific cellular kinase pathways [i.e., mitogen extracellular kinase (MEK)], showing activity against influenza and other viruses; and (x) two structurally unrelated compounds (i.e., LJ-001 and dUY11) with broad-spectrum activity against virtually all enveloped RNA and DNA viruses. © 2012 Wiley Periodicals, Inc.

  1. DOMESTIC SPECTRUM OF ANTIVIRAL DRUG — UMIFENOVIR AS ETIOTROPIC THERAPY OF INFLUENZA

    Directory of Open Access Journals (Sweden)

    L. V. Osidak

    2016-01-01

    Full Text Available In this article are presented the results of comparative observation of the effectiveness of the inclusion in the complex therapy of 203 hospitalized children aged 2 years and older with influenza А(Н1N1pdm09 domestic antiviral drug — Umifenovir  (Arbidol that occurred during the epidemic seasons 2009—2013 and 2015—2016 in terms of observational clinical studies.  It is shown  that this drug, possessing a wide spectrum of antiviral activity, including against Oseltamivir — and Zanamivir-resistant influenza virus strains, antioxidant activity and low toxicity (Code ATX Ј05АХ13, can be successfully used in the treatment of infants with influenza А(Н1N1pdm09.

  2. Antiviral activity of cationic amphiphilic drugs.

    Science.gov (United States)

    Salata, Cristiano; Calistri, Arianna; Parolin, Cristina; Baritussio, Aldo; Palù, Giorgio

    2017-05-01

    Emerging and reemerging viral infections represent a major concern for human and veterinary public health and there is an urgent need for the development of broad-spectrum antivirals. Areas covered: A recent strategy in antiviral research is based on the identification of molecules targeting host functions required for infection of multiple viruses. A number of FDA-approved drugs used to treat several human diseases are cationic amphiphilic drugs (CADs) that have the ability to accumulate inside cells affecting several structures/functions hijacked by viruses during infection. In this review we summarized the CADs' chemical properties and effects on the cells and reported the main FDA-approved CADs that have been identified so far as potential antivirals in drug repurposing studies. Expert commentary: Although there have been concerns regarding the efficacy and the possible side effects of the off-label use of CADs as antivirals, they seem to represent a promising starting point for the development of broad-spectrum antiviral strategies. Further knowledge about their mechanism of action is required to improve their antiviral activity and to reduce the risk of side effects.

  3. Thrombocytopenia from combination treatment with oseltamivir and probenecid: case report, MedWatch data summary, and review of the literature.

    Science.gov (United States)

    Raisch, Dennis W; Straight, Timothy M; Holodniy, Mark

    2009-08-01

    The possibility of an avian flu pandemic has spurred interest in preventive treatments with antivirals such as oseltamivir. Combining treatment with probenecid to delay excretion may extend limited supplies of oseltamivir. We previously conducted a pharmacokinetic study of oseltamivir plus probenecid among healthy volunteers. In this article, we describe a 68-year-old woman who, during the pharmacokinetic study, developed severe thrombocytopenia 2 weeks after starting oseltamivir plus probenecid. She was receiving no other drug therapy at the time. Her platelet count decreased from 200 to 15 x 10(3)/mm(3), although no clinically evident bleeding abnormalities were noted. The two drugs were discontinued. One week later, without any therapeutic intervention, her platelet count returned to normal. By using the Naranjo adverse drug reaction probability scale to assess the strength of the association between the drugs and the adverse event, a score of 7 was derived for both drugs, indicating that the association was probable. We found no previous literature reports of thrombocytopenia associated with either drug. However, a review of the United States Food and Drug Administration's Adverse Event Reporting System database found 93 cases of thrombocytopenia and/or decreased platelet counts associated with oseltamivir and 24 cases associated with probenecid administration. Signal detection analyses were significant for oseltamivir (p=0.001), but not probenecid. The underlying mechanism of thrombocytopenia with these drugs is unknown. Clinicians should be aware that the use of oseltamivir and probenecid has been reported to be associated with thrombocytopenia.

  4. 76 FR 62418 - Antiviral Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2011-10-07

    ...] Antiviral Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS. ACTION... Administration (FDA). The meeting will be open to the public. Name of Committee: Antiviral Drugs Advisory... enter through Building 1. Contact Person: Paul Tran, Center for Drug Evaluation and Research, Food and...

  5. 75 FR 16151 - Antiviral Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2010-03-31

    ...] Antiviral Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS. ACTION... Administration (FDA). The meeting will be open to the public. Name of Committee: Antiviral Drugs Advisory... phone number is 301-589- 5200. Contact Person: Paul Tran, Center for Drug Evaluation and Research (HFD...

  6. 77 FR 15110 - Antiviral Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2012-03-14

    ...] Antiviral Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS. ACTION... Administration (FDA). The meeting will be open to the public. Name of Committee: Antiviral Drugs Advisory... enter through Building 1. Contact Person: Yvette Waples, Center for Drug Evaluation and Research, Food...

  7. 78 FR 56900 - Antiviral Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2013-09-16

    ...] Antiviral Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS. ACTION... Administration (FDA). The meeting will be open to the public. Name of Committee: Antiviral Drugs Advisory..., Center for Drug Evaluation and Research, 10903 New Hampshire Ave., Bldg. 31, Rm. 2417, Silver Spring, MD...

  8. 77 FR 17487 - Antiviral Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2012-03-26

    ...] Antiviral Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS. ACTION... Administration (FDA). The meeting will be open to the public. Name of Committee: Antiviral Drugs Advisory... Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 31, Rm. 2417, Silver...

  9. Oseltamivir storage, distribution and dispensing following the 2009 H1N1 influenza outbreak in Mexico.

    Science.gov (United States)

    Gutiérrez-Mendoza, Luis Meave; Schwartz, Brian; Méndez de Lira, José de Jesús; Wirtz, Veronika J

    2012-10-01

    During an influenza outbreak or pandemic, timely access to antivirals is essential to reduce disease severity and transmission. Best practices in antiviral procurement, storage, distribution, prescription and dispensing must be followed for prompt drug delivery. Mexico implemented a national pandemic preparedness plan in 2006 and created a strategic antiviral stockpile. Oseltamivir powder was stored centrally in bulk for distribution to all 31 states and the capital district during an influenza outbreak. San Luis Potosí, in northern Mexico, was one of the states most intensely affected by the 2009 H1N1 influenza outbreak. The oseltamivir powder was meant to be reconstituted locally but had to be reconstituted centrally during the 2009 influenza outbreak. Doubts arose surrounding the shelf-life of the reconstituted product. As a result of these problems, the first supply of the drug reached San Luis Potosí 11 days after the influenza outbreak had begun. Furthermore, dispensing criteria at the state level had to be changed in conformity with the availability of oseltamivir. Antiviral demand forecasts should be based on clearly defined distribution and dispensing criteria and decentralization of some of the medication stockpile should be considered. Mexico's national pandemic preparedness plan needs to be updated in accordance with the lessons learnt in 2009 to improve strategic stockpile management and ensure rapid delivery of oseltamivir to the population.

  10. 76 FR 14027 - Antiviral Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2011-03-15

    ...] Antiviral Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS. ACTION... Administration (FDA). The meeting will be open to the public. Name of Committee: Antiviral Drugs Advisory... liver disease who are previously untreated or who have failed previous therapy. Compensated liver...

  11. 76 FR 14026 - Antiviral Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2011-03-15

    ...] Antiviral Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS. ACTION... Administration (FDA). The meeting will be open to the public. Name of Committee: Antiviral Drugs Advisory... who are previously untreated or who have failed previous therapy. Compensated liver disease is a stage...

  12. Compliance to oseltamivir among two populations in Oxfordshire, United Kingdom affected by influenza A(H1N1pdm09, November 2009--a waste water epidemiology study.

    Directory of Open Access Journals (Sweden)

    Andrew C Singer

    Full Text Available Antiviral provision remains the focus of many pandemic preparedness plans, however, there is considerable uncertainty regarding antiviral compliance rates. Here we employ a waste water epidemiology approach to estimate oseltamivir (Tamiflu® compliance. Oseltamivir carboxylate (oseltamivir's active metabolite was recovered from two waste water treatment plant (WWTP catchments within the United Kingdom at the peak of the autumnal wave of the 2009 Influenza A (H1N1pdm09 pandemic. Predictions of oseltamivir consumption from detected levels were compared with two sources of national government statistics to derive compliance rates. Scenario and sensitivity analysis indicated between 3-4 and 120-154 people were using oseltamivir during the study period in the two WWTP catchments and a compliance rate between 45-60%. With approximately half the collected antivirals going unused, there is a clear need to alter public health messages to improve compliance. We argue that a near real-time understanding of drug compliance at the scale of the waste water treatment plant (hundreds to millions of people can potentially help public health messages become more timely, targeted, and demographically sensitive, while potentially leading to less mis- and un-used antiviral, less wastage and ultimately a more robust and efficacious pandemic preparedness plan.

  13. 78 FR 57166 - Antiviral Drugs Advisory Committee; Notice of Meeting

    Science.gov (United States)

    2013-09-17

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-N-0001] Antiviral Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS. ACTION: Notice. This notice announces a forthcoming meeting of a public advisory committee of the Food and Drug...

  14. ["Oseltamivir-induced delirium"].

    Science.gov (United States)

    Kruker, Anna Tina; Krause, Martin

    2010-12-01

    We report the history of a religion teacher who was hospitalized in December 2009 during the H1N1 outbreak at our hospital. The 62-year-old man presented in the emergency room with malaise, high fevers and dyspnea. Relevant findings included rales over both lungs, an elevated CRP and a chest x-ray with bilateral interstitial infiltrates suggesting a H1N1 pneumonia. His comorbidities included coronary and hypertensive heart disease, diabetes mellitus Type 2 and chronic renal insufficiency. Although H1N1 virus was not detected by PCR in the nasopharyngeal swabs, Oseltamivir 2 × 75 mg/die was begun and continued for 4 days. His breathing and general condition improved markedly. However, a delirium with psychotic and paranoid symptoms developed which persisted after discharge at home. There, they almost led to a catastrophic event. Although the infection could have been the cause of the delirious state, we propose that it was caused by Oseltamivir. Neuropsychiatric symptoms have been reported in case reports with Oseltamivir, however, this side effect was not specifically investigated when the drug was evaluated.

  15. Oseltamivir and Neuropsychiatric Behaviors – A Case Report on an Adolescent Teen and Evaluation of the Literature

    Directory of Open Access Journals (Sweden)

    Tsz-Yin SO

    2009-11-01

    Full Text Available OBJECTIVE: To illustrate a case of oseltamivir induced neuropsychiatric behaviors in an adolescent teen. CASE SUMMARY: A 15-year-old previously healthy adolescent presented to the emergency department with acute onset of altered mental status after taking two doses of oseltamivir prescribed to him by his primary care physician for presumed influenza infection. A thorough examination at the hospital, which included a urine drug screen, complete blood count, complete metabolic panel, urine and blood cultures, head computed tomography, and chest radiograph, did not indicate any other clinical conditions that could explain his abnormal behaviors. No other medications were given to him in the hospital. About 20 hours after the last dose of oseltamivir, he awoke from a nap and his mental status was completely back to baseline. He had no memory of the events transpired in the past 24 hours and was discharged home with no further incidence.DISSCUSION: Oseltamivir is an anti-viral agent that is often used as treatment and prophylaxis for influenza infection. Neuropsychiatric adverse events such as hallucination and delirium can potentially occur with this agent. This rare adverse event may be due to the binding of the medication to the enzyme sialidase causing increase in dopamine activity. Most of the reports were in young Japanese children less than 16 years old. Some studies have shown a causal relationship with oseltamivir leading to this adverse event, while some have failed to do so, probably due to flaws in their analytical method. The Naranjo ADR probability scale showed a possible causality between neuropsychiatric behaviors and oseltamivir administration in this patient.CONCLUSIONS: Oseltamivir is an effective anti-viral for influenza infection if started early in the course of the illness. Clinicians should monitor for neuropsychiatric symptoms when starting patients on this medication.

  16. Antiviral drug resistance of herpes simplex virus

    NARCIS (Netherlands)

    Stranska, Ruzena

    2004-01-01

    Infections with herpes simplex virus (HSV) usually have an asymptomatic or benign course. However, severe infections do occur, particularly in HIV/AIDS patients or transplant recipients, and may be life-threatening unless adequate antiviral therapy is given. Since its introduction in the early

  17. Population pharmacokinetics of oseltamivir when coadministered with probenecid.

    Science.gov (United States)

    Rayner, Craig R; Chanu, Pascal; Gieschke, Ronald; Boak, Lauren M; Jonsson, E Niclas

    2008-08-01

    Oseltamivir is a potent, selective, oral neuraminidase inhibitor for the treatment and prophylaxis of influenza. Plasma concentrations of the active metabolite, oseltamivir carboxylate, are increased in the presence of probenecid, suggesting that the combination could allow for the use of reduced doses of oseltamivir. To investigate this proposal, we developed a population pharmacokinetic model and simulated the pharmacokinetics of candidate combination regimens of oral oseltamivir (45 mg and 30 mg twice a day) plus oral probenecid (500 mg/6 hourly). Probenecid plus oseltamivir 45 mg achieved all the pharmacokinetic parameters expected of oseltamivir alone, but combination with oseltamivir 30 mg and dose interval extension approaches did not. An oseltamivir-probenecid combination may compromise tolerability and enhance the potential for drug interactions. In addition, increased dosing requirements may affect compliance and attainment of optimal oseltamivir exposure, potentially facilitating the emergence of viral strains with reduced susceptibility to oseltamivir. These factors, set alongside increased capacity for oseltamivir production, should be carefully considered before an oseltamivir-probenecid combination is used.

  18. Aminoadamantanes versus other antiviral drugs for chronic hepatitis C

    DEFF Research Database (Denmark)

    Lamers, Mieke H; Broekman, Mark; Drenth, Joost Ph

    2014-01-01

    months after the end of treatment) in approximately 40% to 80% of treated patients, depending on viral genotype. Recently, a new class of drugs have emerged for hepatitis C infection, the direct acting antivirals, which in combination with standard therapy or alone can lead to sustained virological...... response in 80% or more of treated patients. Aminoadamantanes, mostly amantadine, are antiviral drugs used for the treatment of patients with chronic hepatitis C. We have previously systematically reviewed amantadine versus placebo or no intervention and found no significant effects of the amantadine...... on all-cause mortality or liver-related morbidity and on adverse events in patients with hepatitis C. Overall, we did not observe a significant effect of amantadine on sustained virological response. In this review, we systematically review aminoadamantanes versus other antiviral drugs. OBJECTIVES...

  19. The Combined Effect of Oseltamivir and Favipiravir on Influenza A Virus Evolution.

    Science.gov (United States)

    Ormond, Louise; Liu, Ping; Matuszewski, Sebastian; Renzette, Nicholas; Bank, Claudia; Zeldovich, Konstantin; Bolon, Daniel N; Kowalik, Timothy F; Finberg, Robert W; Jensen, Jeffrey D; Wang, Jennifer P

    2017-07-01

    Influenza virus inflicts a heavy death toll annually and resistance to existing antiviral drugs has generated interest in the development of agents with novel mechanisms of action. Favipiravir is an antiviral drug that acts by increasing the genome-wide mutation rate of influenza A virus (IAV). Potential synergistic benefits of combining oseltamivir and favipiravir have been demonstrated in animal models of influenza, but the population-level effects of combining the drugs are unknown. In order to elucidate the underlying evolutionary processes at play, we performed genome-wide sequencing of IAV experimental populations subjected to serial passaging in vitro under a combined protocol of oseltamivir and favipiravir. We describe the interplay between mutation, selection, and genetic drift that ultimately culminates in population extinction. In particular, selective sweeps around oseltamivir resistance mutations reduce genome-wide variation while deleterious mutations hitchhike to fixation given the increased mutational load generated by favipiravir. This latter effect reduces viral fitness and accelerates extinction compared with IAV populations treated with favipiravir alone, but risks spreading both established and newly emerging mutations, including possible drug resistance mutations, if transmission occurs before the viral populations are eradicated. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  20. Compliance to Oseltamivir among Two Populations in Oxfordshire, United Kingdom Affected by Influenza A(H1N1)pdm09, November 2009 – A Waste Water Epidemiology Study

    Science.gov (United States)

    Singer, Andrew C.; Järhult, Josef D.; Grabic, Roman; Khan, Ghazanfar A.; Fedorova, Ganna; Fick, Jerker; Lindberg, Richard H.; Bowes, Michael J.; Olsen, Björn; Söderström, Hanna

    2013-01-01

    Antiviral provision remains the focus of many pandemic preparedness plans, however, there is considerable uncertainty regarding antiviral compliance rates. Here we employ a waste water epidemiology approach to estimate oseltamivir (Tamiflu®) compliance. Oseltamivir carboxylate (oseltamivir's active metabolite) was recovered from two waste water treatment plant (WWTP) catchments within the United Kingdom at the peak of the autumnal wave of the 2009 Influenza A (H1N1)pdm09 pandemic. Predictions of oseltamivir consumption from detected levels were compared with two sources of national government statistics to derive compliance rates. Scenario and sensitivity analysis indicated between 3–4 and 120–154 people were using oseltamivir during the study period in the two WWTP catchments and a compliance rate between 45–60%. With approximately half the collected antivirals going unused, there is a clear need to alter public health messages to improve compliance. We argue that a near real-time understanding of drug compliance at the scale of the waste water treatment plant (hundreds to millions of people) can potentially help public health messages become more timely, targeted, and demographically sensitive, while potentially leading to less mis- and un-used antiviral, less wastage and ultimately a more robust and efficacious pandemic preparedness plan. PMID:23613721

  1. Assessing the oseltamivir-induced resistance risk and implications for influenza infection control strategies

    Directory of Open Access Journals (Sweden)

    Hsieh NH

    2017-07-01

    Full Text Available Nan-Hung Hsieh,1 Yi-Jun Lin,2 Ying-Fei Yang,2 Chung-Min Liao2 1Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA; 2Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, Taiwan Background: Oseltamivir-resistant mutants with higher drug resistance rates and low transmission fitness costs have not accounted for influenza (subtype viruses. Predicting the impacts of neuraminidase inhibitor therapy on infection rates and transmission of drug-resistant viral strains requires further investigation.Objectives: The purpose of this study was to assess the potential risk of oseltamivir-induced resistance for influenza A (H1N1 and A (H3N2 viruses.Materials and methods: An immune-response-based virus dynamic model was used to best fit the oseltamivir-resistant A (H1N1 and A (H3N2 infection data. A probabilistic risk assessment model was developed by incorporating branching process-derived probability distribution of resistance to estimate oseltamivir-induced resistance risk.Results: Mutation rate and sensitive strain number were key determinants in assessing resistance risk. By increasing immune response, antiviral efficacy, and fitness cost, the spread of resistant strains for A (H1N1 and A (H3N2 were greatly decreased. Probability of resistance depends most strongly on the sensitive strain number described by a Poisson model. Risk of oseltamivir-induced resistance increased with increasing the mutation rate for A (H1N1 only. The ≥50% of resistance risk induced by A (H1N1 and A (H3N2 sensitive infected cells were 0.4 (95% CI: 0.28–0.43 and 0.95 (95% CI 0.93–0.99 at a mutation rate of 10−6, respectively. Antiviral drugs must be administrated within 1–1.5 days for A (H1N1 and 2–2.5 days for A (H3N2 virus infections to limit viral production.Conclusion: Probabilistic risk assessment of antiviral drug

  2. INVESTMENT IN ANTIVIRAL DRUGS : A REAL OPTIONS APPROACH

    NARCIS (Netherlands)

    Attema, Arthur E.; Lugner, Anna K.; Feenstra, Talitha L.

    2010-01-01

    Real options analysis is a promising approach to model investment under uncertainty. We employ this approach to value stockpiling of antiviral drugs as a precautionary measure against a possible influenza pandemic. Modifications of the real options approach to include risk attitude and deviations

  3. Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue.

    Science.gov (United States)

    Incecayir, Tuba; Sun, Jing; Tsume, Yasuhiro; Xu, Hao; Gose, Tomoka; Nakanishi, Takeo; Tamai, Ikumi; Hilfinger, John; Lipka, Elke; Amidon, Gordon L

    2016-02-01

    The goal of this study was to improve the intestinal mucosal cell membrane permeability of the poorly absorbed guanidino analogue of a neuraminidase inhibitor, oseltamivir carboxylate (GOC) using a carrier-mediated strategy. Valyl amino acid prodrug of GOC with isopropyl-methylene-dioxy linker (GOC-ISP-Val) was evaluated as the potential substrate for intestinal oligopeptide transporter, hPEPT1 in Xenopus laevis oocytes heterologously expressing hPEPT1, and an intestinal mouse perfusion system. The diastereomers of GOC-ISP-Val were assessed for chemical and metabolic stability. Permeability of GOC-ISP-Val was determined in Caco-2 cells and mice. Diastereomer 2 was about 2 times more stable than diastereomer 1 in simulated intestinal fluid and rapidly hydrolyzed to the parent drug in cell homogenates. The prodrug had a 9 times-enhanced apparent permeability (P(app)) in Caco-2 cells compared with the parent drug. Both diastereomer exhibited high effective permeability (P(eff)) in mice, 6.32 ± 3.12 and 5.20 ± 2.81 × 10(-5) cm/s for diastereomer 1 and 2, respectively. GOC-ISP-Val was found to be a substrate of hPEPT1. Overall, this study indicates that the prodrug, GOC-ISP-Val, seems to be a promising oral anti-influenza agent that has sufficient stability at physiologically relevant pHs before absorption, significantly improved permeability via hPEPT1 and potentially rapid activation in the intestinal cells. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  4. Novel drugs targeting Toll-like receptors for antiviral therapy.

    Science.gov (United States)

    Patel, Mira C; Shirey, Kari Ann; Pletneva, Lioubov M; Boukhvalova, Marina S; Garzino-Demo, Alfredo; Vogel, Stefanie N; Blanco, Jorge Cg

    2014-09-01

    Toll-like receptors (TLRs) are sentinel receptors of the host innate immune system that recognize conserved 'pathogen-associated molecular patterns' of invading microbes, including viruses. The activation of TLRs establishes antiviral innate immune responses and coordinates the development of long-lasting adaptive immunity in order to control viral pathogenesis. However, microbe-induced damage to host tissues may release 'danger-associated molecular patterns' that also activate TLRs, leading to an overexuberant inflammatory response and, ultimately, to tissue damage. Thus, TLRs have proven to be promising targets as therapeutics for the treatment of viral infections that result in inflammatory damage or as adjuvants in order to enhance the efficacy of vaccines. Here, we explore recent advances in TLR biology with a focus on novel drugs that target TLRs (agonists and antagonists) for antiviral therapy.

  5. Antiviral resistance and the control of pandemic influenza.

    Directory of Open Access Journals (Sweden)

    Marc Lipsitch

    2007-01-01

    Full Text Available The response to the next influenza pandemic will likely include extensive use of antiviral drugs (mainly oseltamivir, combined with other transmission-reducing measures. Animal and in vitro studies suggest that some strains of influenza may become resistant to oseltamivir while maintaining infectiousness (fitness. Use of antiviral agents on the scale anticipated for the control of pandemic influenza will create an unprecedented selective pressure for the emergence and spread of these strains. Nonetheless, antiviral resistance has received little attention when evaluating these plans.We designed and analyzed a deterministic compartmental model of the transmission of oseltamivir-sensitive and -resistant influenza infections during a pandemic. The model predicts that even if antiviral treatment or prophylaxis leads to the emergence of a transmissible resistant strain in as few as 1 in 50,000 treated persons and 1 in 500,000 prophylaxed persons, widespread use of antivirals may strongly promote the spread of resistant strains at the population level, leading to a prevalence of tens of percent by the end of a pandemic. On the other hand, even in circumstances in which a resistant strain spreads widely, the use of antivirals may significantly delay and/or reduce the total size of the pandemic. If resistant strains carry some fitness cost, then, despite widespread emergence of resistance, antivirals could slow pandemic spread by months or more, and buy time for vaccine development; this delay would be prolonged by nondrug control measures (e.g., social distancing that reduce transmission, or use of a stockpiled suboptimal vaccine. Surprisingly, the model suggests that such nondrug control measures would increase the proportion of the epidemic caused by resistant strains.The benefits of antiviral drug use to control an influenza pandemic may be reduced, although not completely offset, by drug resistance in the virus. Therefore, the risk of resistance

  6. [Naturally occurring oseltamivir resistance in influenza A.

    DEFF Research Database (Denmark)

    Madsen, Laura; Nielsen, Alex; Lundgren, Jens

    2010-01-01

    in the development of resistance. The best prevention strategy remains vaccination of the general population to avoid immunity. Future antiviral treatment calls for knowledge about resistance to existing types of influenza and the availability of all three types of antiviral medication. Udgivelsesdato: 2010-Aug......During the last two influenza seasons, one of the predominant influenza A types (H1N1) has developed complete resistance to oseltamivir, the primary treatment option. The virus does, however, remain sensitive to zanamavir and amantadine. There is no unequivocal explanation for this slide...

  7. [Naturally occurring oseltamivir resistance in influenza A.

    DEFF Research Database (Denmark)

    Madsen, Laura; Nielsen, Alex; Lundgren, Jens

    2010-01-01

    During the last two influenza seasons, one of the predominant influenza A types (H1N1) has developed complete resistance to oseltamivir, the primary treatment option. The virus does, however, remain sensitive to zanamavir and amantadine. There is no unequivocal explanation for this slide...... in the development of resistance. The best prevention strategy remains vaccination of the general population to avoid immunity. Future antiviral treatment calls for knowledge about resistance to existing types of influenza and the availability of all three types of antiviral medication. Udgivelsesdato: 2010-Aug...

  8. Antiviral drug profile of human influenza A & B viruses circulating in India: 2004-2011

    Directory of Open Access Journals (Sweden)

    V A Potdar

    2014-01-01

    Full Text Available Background & objectives: Recent influenza antiviral resistance studies in South East Asia, Europe and the United States reveal adamantane and neuraminidase inhibitor (NAIs resistance. This study was undertaken to evaluate antiviral resistance in influenza viruses isolated from various parts of India, during 2004 to 2011. Methods: Influenza viruses were analyzed genetically for known resistance markers by M2 and NA gene sequencing. Influenza A/H1N1 (n=206, A/H3N2 (n=371 viruses for amantadine resistance and A/H1N1 (n=206, A/H3N2 (n=272 and type B (n=326 for oseltamivir resistance were sequenced. Pandemic (H1N1 (n= 493 isolates were tested for H274Y mutation by real time reverse transcription (rRT-PCR. Randomly selected resistant and sensitive influenza A/H1N1 and A/H3N2 viruses were confirmed by phenotypic assay. Results: Serine to asparagine (S3IN mutation was detected in six isolates of 2007-2008.One dual-resistant A/H1N1 was detected for the first time in India with leucine to phenylalanine (L26F mutation in M2 gene and H274Y mutation in NA gene. A/H3N2 viruses showed an increase in resistance to amantadine from 22.5 per cent in 2005 to 100 per cent in 2008 onwards with S3IN mutation. Fifty of the 61 (82% A/H1N1 viruses tested in 2008-2009 were oseltamivir resistant with H274Y mutation, while all A/H3N2, pandemic A/H1N1 and type B isolates remained sensitive. Genetic results were also confirmed by phenotypic analysis of randomly selected 50 resistant A/H1N1 and 40 sensitive A/H3N2 isolates. Interpretation & conclusions: Emergence of influenza viruses resistant to amantadine and oseltamivir in spite of negligible usage of antivirals emphasizes the need for continuous monitoring of antiviral resistance.

  9. NEOGLYCOPROTEINS AS CARRIERS FOR ANTIVIRAL DRUGS - SYNTHESIS AND ANALYSIS OF PROTEIN DRUG CONJUGATES

    NARCIS (Netherlands)

    Molema, Grietje; Jansen, Robert W.; Visser, Jan; Herdewijn, Piet; Moolenaar, Frits; Meijer, Dirk K.F.

    In order to investigate whether neoglycoproteins can potentially act as carriers for targeting of antiviral drugs to certain cell types in the body, various neoglycoproteins were synthesized using thiophosgene-activated p-aminophenyl sugar derivatives. These neoglycoproteins were conjugated with the

  10. Oseltamivir-Resistant Flu

    Centers for Disease Control (CDC) Podcasts

    2012-04-13

    Dr. Aaron Storms, an Epidemic Intelligence Service (EIS) officer at CDC, discusses his paper about oseltamivir-resistant H1N1flu.  Created: 4/13/2012 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 4/17/2012.

  11. SOME ASPECTS OF THE MARKETING STUDIES FOR THE PHARMACEUTICAL MARKET OF ANTIVIRAL DRUGS

    Directory of Open Access Journals (Sweden)

    A. G. Salnikova

    2015-01-01

    Full Text Available Antiviral drugs are widely used in medicinal practice. They suppress the originator and stimulate the protection of an organism. The drugs are used for the treatment of flu and ARVI, herpetic infections, virus hepatitis, HIV-infection. Contemporary pharmaceutical market is represented by a wide range of antiviral drugs. Marketing studies are conducted to develop strategies, used for the enhancement of pharmacy organization activity efficiency. Conduction of the marketing researches of pharmaceutical market is the purpose of this study. We have used State Registry of Drugs, State Record of Drugs, List of vital drugs, questionnaires of pharmaceutical workers during our work. Historical, sociological, mathematical methods, and a method of expert evaluation were used in the paper. As the result of the study we have made the following conclusions. We have studied and generalized the literature data about classification and application of antiviral drugs, marketing, competition. The assortment of antiviral drugs on the pharmaceutical market of the Russian Federation was also studied. We have conducted an analysis for the obtainment of the information about antiviral drugs by pharmaceutical workers. We have determined the competitiveness of antiviral drugs, and on the basis of the research conducted we have submitted an offer for pharmaceutical organizations to form the range of antiviral drugs.

  12. Bell's Palsy: Treatment with Steroids and Antiviral Drugs

    Science.gov (United States)

    ... Drooping of a corner of the mouth • Difficulty smiling, frowning, or making other facial expressions • Twitching or ... no definite added improvement. If there is any benefit to adding an antiviral to steroid treatment, it ...

  13. Mathematical modeling of multi-drugs therapy: a challenge for determining the optimal combinations of antiviral drugs.

    Science.gov (United States)

    Koizumi, Yoshiki; Iwami, Shingo

    2014-09-25

    In the current era of antiviral drug therapy, combining multiple drugs is a primary approach for improving antiviral effects, reducing the doses of individual drugs, relieving the side effects of strong antiviral drugs, and preventing the emergence of drug-resistant viruses. Although a variety of new drugs have been developed for HIV, HCV and influenza virus, the optimal combinations of multiple drugs are incompletely understood. To optimize the benefits of multi-drugs combinations, we must investigate the interactions between the combined drugs and their target viruses. Mathematical models of viral infection dynamics provide an ideal tool for this purpose. Additionally, whether drug combinations computed by these models are synergistic can be assessed by two prominent drug combination theories, Loewe additivity and Bliss independence. By combining the mathematical modeling of virus dynamics with drug combination theories, we could show the principles by which drug combinations yield a synergistic effect. Here, we describe the theoretical aspects of multi-drugs therapy and discuss their application to antiviral research.

  14. The majority of hepatitis C patients treated with direct acting antivirals are at risk for relevant drug-drug interactions.

    Science.gov (United States)

    Smolders, Elise J; Berden, Floor Ac; de Kanter, Clara Tmm; Kievit, Wietske; Drenth, Joost Ph; Burger, David M

    2017-08-01

    Direct-acting antivirals have improved treatment of chronic hepatitis C virus infection significantly. Direct-acting antivirals inhibit/induce and can also be substrates of drug-metabolising enzymes and transporters. This increases the risk for drug-drug interactions. The purpose of this study was to predict drug-drug interactions with co-medication used by hepatitis C virus-infected patients. We assembled a nationwide cohort of hepatitis C patients and collected cross-sectional data on co-medication use. We compiled a list of currently available direct-acting antiviral regimens and cross-checked for potential drug-drug interactions with used co-medication. The cohort included 461 patients of which 77% used co-medication. We identified 260 drugs used as co-medication. Antidepressants (7.4%), proton pump inhibitors (7.1%) and benzodiazepines (7.1%) were most frequently used. Of the patients, 60% were at risk for a clinically relevant drug-drug interaction with at least one of the direct-acting antiviral regimens. Interactions were most common with paritaprevir/ritonavir/ombitasvir/dasabuvir and least interactions were predicted with grazoprevir/elbasvir. Co-medication use is rich in frequency and diversity in chronic hepatitis C patients. The majority of patients are at risk for drug-drug interactions which may affect efficacy or toxicity of direct-acting antivirals or co-medication. The most recently introduced direct-acting antivirals are associated with a lower risk of drug-drug interactions.

  15. Determining the Quality of Oseltamivir (Tamiflu)

    Centers for Disease Control (CDC) Podcasts

    2008-02-04

    The possibility of an avian flu pandemic has given Tamiflu attention. Because of fear of a pandemic, this drug has been in high demand. Unfortunately, this demand has prompted production of counterfeit Tamiflu. CDC's Dr. Mike Green discusses a test that is simple and affordable and can test the quality of products purported to be oseltamivir (Tamiflu).  Created: 2/4/2008 by Emerging Infectious Diseases.   Date Released: 2/20/2008.

  16. Pharmacokinetics and tolerability of oseltamivir combined with probenecid.

    Science.gov (United States)

    Holodniy, Mark; Penzak, Scott R; Straight, Timothy M; Davey, Richard T; Lee, Kelvin K; Goetz, Matthew Bidwell; Raisch, Dennis W; Cunningham, Francesca; Lin, Emil T; Olivo, Noemi; Deyton, Lawrence R

    2008-09-01

    Oseltamivir is an inhibitor of influenza virus neuraminidase, which is approved for use for the treatment and prophylaxis of influenza A and B virus infections. In the event of an influenza pandemic, oseltamivir supplies may be limited; thus, alternative dosing strategies for oseltamivir prophylaxis should be explored. Healthy volunteers were randomized to a three-arm, open-label study and given 75 mg oral oseltamivir every 24 h (group 1), 75 mg oseltamivir every 48 h (q48h) combined with 500 mg probenecid four times a day (group 2), or 75 mg oseltamivir q48h combined with 500 mg probenecid twice a day (group 3) for 15 days. Pharmacokinetic data, obtained by noncompartmental methods, and safety data are reported. Forty-eight subjects completed the pharmacokinetic analysis. The study drugs were generally well tolerated, except for one case of reversible grade 4 thrombocytopenia in a subject in group 2. The calculated 90% confidence intervals (CIs) for the geometric mean ratios between groups 2 and 3 and group 1 were outside the bioequivalence criteria boundary (0.80 to 1.25) at 0.63 to 0.89 for group 2 versus group 1 and 0.57 to 0.90 for group 3 versus group 1. The steady-state apparent oral clearance of oseltamivir carboxylate was significantly less in groups 2 (7.4 liters/h; 90% CI, 6.08 to 8.71) and 3 (7.19 liters/h; 90% CI, 6.41 to 7.98) than in group 1 (9.75 liters/h; 90% CI, 6.91 to 12.60) (P probenecid four times daily achieved trough oseltamivir carboxylate concentrations adequate for neuraminidase inhibition in vitro, and this combination should be studied further.

  17. Pharmacokinetics and Tolerability of Oseltamivir Combined with Probenecid▿ †

    Science.gov (United States)

    Holodniy, Mark; Penzak, Scott R.; Straight, Timothy M.; Davey, Richard T.; Lee, Kelvin K.; Goetz, Matthew Bidwell; Raisch, Dennis W.; Cunningham, Francesca; Lin, Emil T.; Olivo, Noemi; Deyton, Lawrence R.

    2008-01-01

    Oseltamivir is an inhibitor of influenza virus neuraminidase, which is approved for use for the treatment and prophylaxis of influenza A and B virus infections. In the event of an influenza pandemic, oseltamivir supplies may be limited; thus, alternative dosing strategies for oseltamivir prophylaxis should be explored. Healthy volunteers were randomized to a three-arm, open-label study and given 75 mg oral oseltamivir every 24 h (group 1), 75 mg oseltamivir every 48 h (q48h) combined with 500 mg probenecid four times a day (group 2), or 75 mg oseltamivir q48h combined with 500 mg probenecid twice a day (group 3) for 15 days. Pharmacokinetic data, obtained by noncompartmental methods, and safety data are reported. Forty-eight subjects completed the pharmacokinetic analysis. The study drugs were generally well tolerated, except for one case of reversible grade 4 thrombocytopenia in a subject in group 2. The calculated 90% confidence intervals (CIs) for the geometric mean ratios between groups 2 and 3 and group 1 were outside the bioequivalence criteria boundary (0.80 to 1.25) at 0.63 to 0.89 for group 2 versus group 1 and 0.57 to 0.90 for group 3 versus group 1. The steady-state apparent oral clearance of oseltamivir carboxylate was significantly less in groups 2 (7.4 liters/h; 90% CI, 6.08 to 8.71) and 3 (7.19 liters/h; 90% CI, 6.41 to 7.98) than in group 1 (9.75 liters/h; 90% CI, 6.91 to 12.60) (P probenecid four times daily achieved trough oseltamivir carboxylate concentrations adequate for neuraminidase inhibition in vitro, and this combination should be studied further. PMID:18559644

  18. Antiviral resistance due to deletion in the neuraminidase gene and defective interfering-like viral polymerase basic 2 RNA of influenza A virus subtype H3N2

    DEFF Research Database (Denmark)

    Trebbien, Ramona; Christiansen, Claus Bohn; Fischer, Thea Kølsen

    2018-01-01

    Background and objective: Antiviral treatment of influenza virus infections can lead to drug resistance of virus. This study investigates a selection of mutations in the full genome of H3N2 influenza A virus isolated from a patient in treatment with oseltamivir. Study design: Respiratory samples...... from a patient were collected before, during, and after antiviral treatment. Whole genome sequencing of the influenza virus by next generation sequencing, and low-frequency-variant analysis was performed. Neuraminidase-inhibition tests were performed with oseltamivir and zanamivir, and viruses were......, indicating a potential risk for transmission of the deleted virus. Full genome deep sequencing was useful to reveal variant mutations that might be selected due to antiviral treatment, and defective interfering-like viral PB2 RNA in the respiratory samples was detected....

  19. Combinations of 1,8-cineol and oseltamivir for the treatment of influenza virus A (H3N2) infection in mice.

    Science.gov (United States)

    Lai, Yan-Ni; Li, Yun; Fu, Lin-Chun; Zhao, Fang; Liu, Ni; Zhang, Feng-Xue; Xu, Pei-Ping

    2017-07-01

    It is need for development of new means against influenza virus due to the lack of efficacy of available therapeutic strategies. In previous research, 1,8-cineol exert its inhibition of nuclear factor (NF)-κB, the main regulator of cytokine and chemokine production in influenza, and anti-inflammatory activity. These fact supports and helps establish the hypothesis that 1,8-cineol may have synergism with an antiviral on influenza virus infection. The combined effect of 1,8-cineol with oseltamivir in a mouse type A influenza virus (Victoria/3/75,H3N2) model were examined. We initially tested combinations of 1,8-cineol (30, 60, and 120 mg/kg/day) and oseltamivir (0.1, 0.2, and 0.4 mg/kg/day). In addition, the 0.4 mg/kg/day of oseltamivir combined with 120 mg/kg of 1,8-cineol was selected for further combination studies. Oseltamivir was 30%, 40%, and 60% protective at 0.1, 0.2, and 0.4 mg/kg/d. Combinations of 1,8-cineol (30, 60, and 120 mg/kg/d) and oseltamivir (0.1, 0.2, and 0.4 mg/kg/d) increased the number of survivors and mean survival time (MST) following combination treatment was greater than monotherapy alone. Three dimensional analysis of drug interactions using the MacSynergy method showed a strong synergistic effect of these drug combinations. Survival, MST, lung parameters (lung index, viral titers, and pathology), and cytokines (IL-10, TNF-α, IL-1β, and IFN-γ) expression in lung demonstrated the high effectiveness of the combination. Combined treatment was associated with longer MST and more reduced cytokine levels than oseltamivir alone. These data demonstrate that combinations of 1,8-cineol and oseltamivir have synergistic effect against influenza A virus (H3N2) infection. © 2017 Wiley Periodicals, Inc.

  20. Efficacy of Antiviral Drugs against Feline Immunodeficiency Virus

    Science.gov (United States)

    Hartmann, Katrin; Wooding, Anita; Bergmann, Michèle

    2015-01-01

    Feline immunodeficiency virus (FIV) is one of the most common infectious agents affecting cats worldwide .FIV and human immunodeficiency virus (HIV) share many properties: both are lifelong persistent lentiviruses that are similar genetically and morphologically and both viruses propagate in T-lymphocytes, macrophages, and neural cells. Experimentally infected cats have measurable immune suppression, which sometimes progresses to an acquired immunodeficiency syndrome. A transient initial state of infection is followed by a long latent stage with low virus replication and absence of clinical signs. In the terminal stage, both viruses can cause severe immunosuppression. Thus, FIV infection in cats has become an important natural model for studying HIV infection in humans, especially for evaluation of antiviral compounds. Of particular importance for chemotherapeutic studies is the close similarity between the reverse transcriptase (RT) of FIV and HIV, which results in high in vitro susceptibility of FIV to many RT-targeted antiviral compounds used in the treatment of HIV-infected patients. Thus, the aim of this article is to provide an up-to-date review of studies on antiviral treatment of FIV, focusing on commercially available compounds for human or animal use. PMID:29061953

  1. Efficacy of Antiviral Drugs against Feline Immunodeficiency Virus

    Directory of Open Access Journals (Sweden)

    Katrin Hartmann

    2015-12-01

    Full Text Available Feline immunodeficiency virus (FIV is one of the most common infectious agents affecting cats worldwide .FIV and human immunodeficiency virus (HIV share many properties: both are lifelong persistent lentiviruses that are similar genetically and morphologically and both viruses propagate in T-lymphocytes, macrophages, and neural cells. Experimentally infected cats have measurable immune suppression, which sometimes progresses to an acquired immunodeficiency syndrome. A transient initial state of infection is followed by a long latent stage with low virus replication and absence of clinical signs. In the terminal stage, both viruses can cause severe immunosuppression. Thus, FIV infection in cats has become an important natural model for studying HIV infection in humans, especially for evaluation of antiviral compounds. Of particular importance for chemotherapeutic studies is the close similarity between the reverse transcriptase (RT of FIV and HIV, which results in high in vitro susceptibility of FIV to many RT-targeted antiviral compounds used in the treatment of HIV-infected patients. Thus, the aim of this article is to provide an up-to-date review of studies on antiviral treatment of FIV, focusing on commercially available compounds for human or animal use.

  2. AVALIAÇÃO DO TRATAMENTO REALIZADO COM O ANTIVIRAL FOSFATO DE OSELTAMIVIR (TAMIFLU® E OS EXAMES LABORATORIAIS DE PACIENTES DIAGNOSTICADOS COM GRIPE A SUBTIPO H1N1 EM UM HOSPITAL DA CIDADE DE TOLEDO – PARANÁ, BRASIL

    Directory of Open Access Journals (Sweden)

    Kiara Regina Canzi

    2015-12-01

    Full Text Available O fosfato de oseltamivir, uma pró-droga do carboxilato de oseltamivir, é um inibidor potente e seletivo das enzimas neuraminidase. A atividade da enzima viral, neuraminidase, é importante tanto para a entrada do vírus em células não infectadas quanto para a liberação de partículas virais. O carboxilato de oseltamivir inibe a neuraminidase do vírus da gripe de ambos os tipos: Influenza A e B, impedindo a replicação do mesmo. 46 pacientes com idades entre 1 e 76 anos de idade, de ambos os sexos, internados em um Hospital na cidade de Toledo durante o período de Junho de 2009 a Janeiro de 2010, com casos confirmados ou suspeitos de gripe A subtipo H1N1. Durante o período de internamento, foi avaliado o uso do Fosfato de Oseltamivir, bem como reações adversas e tempo de uso do medicamento e os exames empregados para auxiliar o diagnóstico (Hemograma completo e a gasometria arterial. O tempo de uso do medicamento não excedeu o preconizado, o qual foi de 5 (cinco dias ininterruptos, e entre as reações adversas ou efeitos colaterais estão náusea (43,47%, cefaléia (8,69% e vômitos (17,39%. As alterações laboratoriais evidenciam leucócitos normais (média de 9.145 mL, plaquetas de 246.166 mm³, pH sanguíneo (gasometria arterial levemente ácido e PO2 (mmHg e SO2 abaixo dos valores de referência. A abordagem da infecção pelo vírus Influenza A H1N1 2009 representa desafio epidemiológico-clinico-laboratorial-terapêutico em todo o mundo. Logo, requer esforço coletivo para impedir o seu avanço e os riscos de letalidade e mortalidade incluídos em sua disseminação.

  3. Design Features of Drug-Drug Interaction Trials Between Antivirals and Oral Contraceptives.

    Science.gov (United States)

    Ayala, Ruben C; Arya, Vikram; Younis, Islam R

    2016-05-01

    The aim of this work was to explore the major design features of drug-drug interaction trials between antiviral medications (AVs) and oral contraceptives (OCs). Information on these trials (n = 27) was collected from approved drug labels and clinical pharmacology reviews conducted by the U.S. Food and Drug Administration. The primary objective of all trials was to evaluate changes in OC exposure following the coadministration of AVs. In addition, an evaluation of potential pharmacodynamic interaction was performed in 10 of these trials. Twenty-two trials were open label with a fixed-sequence design, and 5 trials used a double-blind crossover design. The trials were conducted using one, two, or three 28-day ovulatory cycles in 10, 8, and 9 trials, respectively. Only 1 trial enrolled HIV-infected women. The median number of women in a trial was 20 (range, 12 to 52). Norethindrone/ethinyl estradiol (EE) combination was the most commonly used OC (n = 16, 59%) followed by norgestimate/EE (n = 9, 33%). Labeling recommendations were based on exposure changes in 25 cases and on safety observations in the trial in 2 cases. In conclusion, a wide variety of trial designs was used, and there is no preferred design. The answer to the exposure question can be achieved using multiple designs. © 2015, The American College of Clinical Pharmacology.

  4. Nose-to-Brain Delivery of Antiviral Drugs: A Way to Overcome Their Active Efflux?

    Directory of Open Access Journals (Sweden)

    Alessandro Dalpiaz

    2018-03-01

    Full Text Available Although several viruses can easily infect the central nervous system (CNS, antiviral drugs often show dramatic difficulties in penetrating the brain from the bloodstream since they are substrates of active efflux transporters (AETs. These transporters, located in the physiological barriers between blood and the CNS and in macrophage membranes, are able to recognize their substrates and actively efflux them into the bloodstream. The active transporters currently known to efflux antiviral drugs are P-glycoprotein (ABCB1 or P-gp or MDR1, multidrug resistance-associated proteins (ABCC1 or MRP1, ABCC4 or MRP4, ABCC5 or MRP5, and breast cancer resistance protein (ABCG2 or BCRP. Inhibitors of AETs may be considered, but their co-administration causes serious unwanted effects. Nasal administration of antiviral drugs is therefore proposed in order to overcome the aforementioned problems, but innovative devices, formulations (thermoreversible gels, polymeric micro- and nano-particles, solid lipid microparticles, nanoemulsions, absorption enhancers (chitosan, papaverine, and mucoadhesive agents (chitosan, polyvinilpyrrolidone are required in order to selectively target the antiviral drugs and, possibly, the AET inhibitors in the CNS. Moreover, several prodrugs of antiretroviral agents can inhibit or elude the AET systems, appearing as interesting substrates for innovative nasal formulations able to target anti-Human Immunodeficiency Virus (HIV agents into macrophages of the CNS, which are one of the most important HIV Sanctuaries of the body.

  5. Investment decisions in influenza pandemic contingency planning : cost-effectiveness of stockpiling antiviral drugs

    NARCIS (Netherlands)

    Lugner, Anna K.; Postma, Maarten J.

    2009-01-01

    Background: The threat of an influenza pandemic has led to stockpiling of antiviral drugs in order to mitigate a plausible outbreak. If the stockpile would be used in relation to the recent pandemic alert, an investment decision about renewing the stock for a possible subsequent pandemic is

  6. A simple, rapid, and sensitive system for the evaluation of anti-viral drugs in rats

    International Nuclear Information System (INIS)

    Li, Xiaoguang; Qian, Hua; Miyamoto, Fusako; Naito, Takeshi; Kawaji, Kumi; Kajiwara, Kazumi; Hattori, Toshio; Matsuoka, Masao; Watanabe, Kentaro; Oishi, Shinya; Fujii, Nobutaka

    2012-01-01

    Highlights: ► We established a novel, simple and rapid in vivo system for evaluation of anti-HIV-1 drugs with rats. ► The system may be applicable for other antiviral drugs, and/or useful for initial screening in vivo. ► In this system, TRI-1144 displayed the most potent anti-HIV-1 activity in vivo. -- Abstract: The lack of small animal models for the evaluation of anti-human immunodeficiency virus type 1 (HIV-1) agents hampers drug development. Here, we describe the establishment of a simple and rapid evaluation system in a rat model without animal infection facilities. After intraperitoneal administration of test drugs to rats, antiviral activity in the sera was examined by the MAGI assay. Recently developed inhibitors for HIV-1 entry, two CXCR4 antagonists, TF14016 and FC131, and four fusion inhibitors, T-20, T-20EK, SC29EK, and TRI-1144, were evaluated using HIV-1 IIIB and HIV-1 BaL as representative CXCR4- and CCR5-tropic HIV-1 strains, respectively. CXCR4 antagonists were shown to only possess anti-HIV-1 IIIB activity, whereas fusion inhibitors showed both anti-HIV-1 IIIB and anti-HIV-1 BaL activities in rat sera. These results indicate that test drugs were successfully processed into the rat sera and could be detected by the MAGI assay. In this system, TRI-1144 showed the most potent and sustained antiviral activity. Sera from animals not administered drugs showed substantial anti-HIV-1 activity, indicating that relatively high dose or activity of the test drugs might be needed. In conclusion, the novel rat system established here, “phenotypic drug evaluation”, may be applicable for the evaluation of various antiviral drugs in vivo.

  7. A simple, rapid, and sensitive system for the evaluation of anti-viral drugs in rats

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xiaoguang [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Department of Medical Microbiology, Harbin Medical University, Harbin 150086 (China); Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811 (Japan); Qian, Hua [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811 (Japan); Miyamoto, Fusako [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Naito, Takeshi [Laboratory of Virus Control, Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Kawaji, Kumi [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Kajiwara, Kazumi [Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); JST Innovation Plaza Kyoto, Japan Science and Technology Agency, Nishigyo-ku, Kyoto 615-8245 (Japan); Hattori, Toshio [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Matsuoka, Masao [Laboratory of Virus Control, Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Watanabe, Kentaro; Oishi, Shinya; Fujii, Nobutaka [Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); and others

    2012-07-27

    Highlights: Black-Right-Pointing-Pointer We established a novel, simple and rapid in vivo system for evaluation of anti-HIV-1 drugs with rats. Black-Right-Pointing-Pointer The system may be applicable for other antiviral drugs, and/or useful for initial screening in vivo. Black-Right-Pointing-Pointer In this system, TRI-1144 displayed the most potent anti-HIV-1 activity in vivo. -- Abstract: The lack of small animal models for the evaluation of anti-human immunodeficiency virus type 1 (HIV-1) agents hampers drug development. Here, we describe the establishment of a simple and rapid evaluation system in a rat model without animal infection facilities. After intraperitoneal administration of test drugs to rats, antiviral activity in the sera was examined by the MAGI assay. Recently developed inhibitors for HIV-1 entry, two CXCR4 antagonists, TF14016 and FC131, and four fusion inhibitors, T-20, T-20EK, SC29EK, and TRI-1144, were evaluated using HIV-1{sub IIIB} and HIV-1{sub BaL} as representative CXCR4- and CCR5-tropic HIV-1 strains, respectively. CXCR4 antagonists were shown to only possess anti-HIV-1{sub IIIB} activity, whereas fusion inhibitors showed both anti-HIV-1{sub IIIB} and anti-HIV-1{sub BaL} activities in rat sera. These results indicate that test drugs were successfully processed into the rat sera and could be detected by the MAGI assay. In this system, TRI-1144 showed the most potent and sustained antiviral activity. Sera from animals not administered drugs showed substantial anti-HIV-1 activity, indicating that relatively high dose or activity of the test drugs might be needed. In conclusion, the novel rat system established here, 'phenotypic drug evaluation', may be applicable for the evaluation of various antiviral drugs in vivo.

  8. Caulerpin as a potential antiviral drug against herpes simplex virus type 1

    Directory of Open Access Journals (Sweden)

    Nathália Regina Porto Vieira Macedo

    2012-08-01

    Full Text Available About 80% of the human adult population is infected with HSV-1. Although there are many anti-HSV-1 drugs available (acyclovir, ganciclovir, valaciclovir, foscarnet, their continuous use promotes the selection of resistant strains, mainly in ACV patients. In addition to resistance, the drugs also have toxicity, particularly when administration is prolonged. The study of new molecules isolated from green algae with potential antiviral activity represents a good opportunity for the development of antiviral drugs. Caulerpin, the major product from the marine algae Caulerpa Lamouroux (Caulerpales, is known for its biological activities such as antioxidant, antifungal, acetylcholinesterase inhibitor (AChE and antibacterial activity. In this work, we show that caulerpin could be an alternative to acyclovir as an anti-HSV-1 drug that inhibits the alpha and beta phases of the replication cycle.

  9. OSELTAMIVIR MEDICATION IN THE PEDIATRIC PRACTICE: THE REVIEW

    Directory of Open Access Journals (Sweden)

    A.B. Ivanyuk

    2008-01-01

    Full Text Available Flu in children is characterized by high incidence, often development of complications, long virus extraction. Measures for its prophylaxis and treatment include the usage of vaccines and etiotropic medications, in particular, those of the neuraminidase inhibitor group which are considered to be efficient and safe in children. Oseltamivir is the most widespread drug of this group in the pediatric practice. The objective of this research was the analysis of foreign works devoted to the use of oseltamivir in children from the evidence based medicine viewpoint. as a result, two multicenter double blind placebo controlled trials were found, which included 1029 children other trials devoted to the study of different aspects of this problem. They showed that in children without co-morbidities, oseltamivir evidentially reducesthe duration of disease, duration of fever, cough, rhinitis and the frequency of complications; in case of bronchial asthma, however, these changes are below statistical significance. Oseltamivir shows high tolerability in children, and adverse events seldom occur.Key words: oseltamivir, neuraminidase inhibitors, children.

  10. Dominant drug targets suppress the emergence of antiviral resistance

    OpenAIRE

    Tanner, Elizabeth J; Liu, Hong-mei; Oberste, M Steven; Pallansch, Mark; Collett, Marc S; Kirkegaard, Karla

    2014-01-01

    eLife digest Treating a viral infection with a drug sometimes has an unwanted side effect?the virus quickly becomes resistant to the drug. Viruses whose genetic information is encoded in molecules of RNA mutate faster than DNA viruses and are particularly good at developing resistance to drugs. This is because the process of copying the RNA is prone to errors, and by chance some of these errors, or mutations, may allow the virus to resist the drug's effects. Treating viral infections with mos...

  11. Filovirus proteins for antiviral drug discovery: Structure/function bases of the replication cycle.

    Science.gov (United States)

    Martin, Baptiste; Canard, Bruno; Decroly, Etienne

    2017-05-01

    Filoviruses are important pathogens that cause severe and often fatal hemorrhagic fever in humans, for which no approved vaccines and antiviral treatments are yet available. In an earlier article (Martin et al., Antiviral Research, 2016), we reviewed the role of the filovirus surface glycoprotein in replication and as a target for drugs and vaccines. In this review, we focus on recent findings on the filovirus replication machinery and how they could be used for the identification of new therapeutic targets and the development of new antiviral compounds. First, we summarize the recent structural and functional advances on the molecules involved in filovirus replication/transcription cycle, particularly the NP, VP30, VP35 proteins, and the "large" protein L, which harbors the RNA-dependent RNA polymerase (RdRp) and mRNA capping activities. These proteins are essential for viral mRNA synthesis and genome replication, and consequently they constitute attractive targets for drug design. We then describe how these insights into filovirus replication mechanisms and the structure/function characterization of the involved proteins have led to the development of new and innovative antiviral strategies that may help reduce the filovirus disease case fatality rate through post-exposure or prophylactic treatments. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Pharmacokinetics of oseltamivir in infants under the age of 1 year.

    Science.gov (United States)

    Dixit, Rashmi; Matthews, Slade; Khandaker, Gulam; Walker, Karen; Festa, Marino; Booy, Robert

    2016-12-01

    Oseltamivir is the only antiviral treatment recommended for influenza in young children over the age of 1 year. There is scant data on oseltamivir pharmacokinetics (PK) in infants clearance in infants time points afterwards, to calculate Cmax (ng/mL), Tmax (h), AUC0-t (ng h/mL) and time for AUC (h). Four children with influenza A received oral oseltamivir, 2.35-3 mg/kg/dose. This dose range produced a target oseltamivir carboxylate plasma concentration in excess of the proposed 12-h target AUC of 3800 ng h/mL, selected from earlier studies to avert resistance. One patient developed GIT adverse event: dry retching. Oseltamivir was well tolerated at a dose of 2.35-3 mg/kg/dose twice a day in infants under the age of 1 year. In general agreement with earlier data, these doses produced a target oseltamivir carboxylate plasma exposure in excess of the proposed 12-h target exposure of AUC equal to 3800 ng h/mL in two patients. The limited plasma concentration data in the remaining two patients were not inconsistent with the target exposure being reached.

  13. Dynamics of an HBV Model with Drug Resistance Under Intermittent Antiviral Therapy

    Science.gov (United States)

    Zhang, Ben-Gong; Tanaka, Gouhei; Aihara, Kazuyuki; Honda, Masao; Kaneko, Shuichi; Chen, Luonan

    2015-06-01

    This paper studies the dynamics of the hepatitis B virus (HBV) model and the therapy regimens of HBV disease. First, we propose a new mathematical model of HBV with drug resistance, and then analyze its qualitative and dynamical properties. Combining the clinical data and theoretical analysis, we demonstrate that our model is biologically plausible and also computationally viable. Second, we demonstrate that the intermittent antiviral therapy regimen is one of the possible strategies to treat this kind of complex disease. There are two main advantages of this regimen, i.e. it not only may delay the development of drug resistance, but also may reduce the duration of on-treatment time compared with the long-term continuous medication. Moreover, such an intermittent antiviral therapy can reduce the adverse side effects. Our theoretical model and computational results provide qualitative insight into the progression of HBV, and also a possible new therapy for HBV disease.

  14. [Antiviral activity of different drugs in vitro against viruses of bovine infectious rhinotracheitis and bovine diarrhea].

    Science.gov (United States)

    Glotov, A G; Glotova, T I; Sergeev, A A; Belkina, T V; Sergeev, A N

    2004-01-01

    In vitro experiments studied the antiviral activity of 11 different drugs against viruses of bovine infective rhinotracheitis (BIRT) and bovine viral diarrhea (BVD). The 50% inhibiting concentrations of the test agents were determined in the monolayers of MDBK and KCT cell cultures. Only did phosprenyl show a virucidal activity against BIRT virus. All the tested drugs significantly inhibited the reproduction of BIRT virus in the sensitive MDBK cell cultures. Thus, bromuridin, acyclovir, ribavirin and methisazonum inhibited the virus by > or = 100,000 times; liposomal ribavirin, gossypolum, anandinum, polyprenolum, phosprenyl, by 1000-10,000 times; eracond and argovit, by 100 times. In experiments on BVD virus, the cultured KCT cells displayed the antiviral activity of bromuridin, phosprenil, polyprenolum, methisazonum, acyclovir, gossypolum, argovit, and ribavirin (in two variants), which caused a statistically significant (100-10,000-fold) decrease in the productive activity of this virus. Eracond and anandid proved to be ineffective.

  15. Indian marine bivalves: Potential source of antiviral drugs

    Digital Repository Service at National Institute of Oceanography (India)

    Chatterji, A.; Ansari, Z.A.; Ingole, B.S.; Bichurina, M.A.; Sovetova, M.; Boikov, Y.A.

    showed 66 ? 84% survival 3 . Administration of extract of mussel in mice, both intranasal and oral, gave signif i cant Table 1. Result of neutralization reaction with fragments of chicken embryo (VCA) with six different e x tracts... in elderly persons. The present investigatio ns showed that marine an i mals have great potential for developing useful drugs. Extra c- tion of important biologically - active compounds from marine resources will certainly be helpful in pr o tecting...

  16. The anti-obesity drug orlistat reveals anti-viral activity.

    Science.gov (United States)

    Ammer, Elisabeth; Nietzsche, Sandor; Rien, Christian; Kühnl, Alexander; Mader, Theresa; Heller, Regine; Sauerbrei, Andreas; Henke, Andreas

    2015-12-01

    The administration of drugs to inhibit metabolic pathways not only reduces the risk of obesity-induced diseases in humans but may also hamper the replication of different viral pathogens. In order to investigate the value of the US Food and Drug Administration-approved anti-obesity drug orlistat in view of its anti-viral activity against different human-pathogenic viruses, several anti-viral studies, electron microscopy analyses as well as fatty acid uptake experiments were performed. The results indicate that administrations of non-cytotoxic concentrations of orlistat reduced the replication of coxsackievirus B3 (CVB3) in different cell types significantly. Moreover, orlistat revealed cell protective effects and modified the formation of multi-layered structures in CVB3-infected cells, which are necessary for viral replication. Lowering fatty acid uptake from the extracellular environment by phloretin administrations had only marginal impact on CVB3 replication. Finally, orlistat reduced also the replication of varicella-zoster virus moderately but had no significant influence on the replication of influenza A viruses. The data support further experiments into the value of orlistat as an inhibitor of the fatty acid synthase to develop new anti-viral compounds, which are based on the modulation of cellular metabolic pathways.

  17. Quantitative autoradiographic mapping of herpes simplex virus encephalitis with a radiolabeled antiviral drug

    International Nuclear Information System (INIS)

    Saito, Y.; Price, R.W.; Rottenberg, D.A.; Fox, J.J.; Su, T.L.; Watanabe, K.A.; Philips, F.S.

    1982-01-01

    2'-Fluoro-5-methyl-1-ν-D-arabinosyluracil (FMAU) labeled with carbon-14 was used to image herpes simplex virus type 1-infected regions of rat brain by quantitative autoradiography. FMAU is a potent antiviral pyrimidine nucleoside which is selectively phosphorylated by virus-coded thymidine kinase. When the labeled FMAU was administered 6 hours before the rats were killed, the selective uptake and concentration of the drug and its metabolites by infected cells (defined by immunoperoxidase staining of viral antigens) allowed quantitative definition and mapping of HSV-1-infected structures in autoradiograms of brain sections. These results shown that quantitative autoradiography can be used to characterize the local metabolism of antiviral drugs by infected cells in vivo. They also suggest that the selective uptake of drugs that exploit viral thymidine kinase for their antiviral effect can, by appropriate labeling, be used in conjunction with clinical neuroimaging techniques to define infected regions of human brain, thereby providing a new approach to the diagnosis of herpes encephalitis in man

  18. Epidemiological characteristics of novel influenza A (H1N1 in antiviral drug users in Korea.

    Directory of Open Access Journals (Sweden)

    Kyunghi Choi

    Full Text Available Soon after the first novel influenza A (H1N1 death was documented in Korea on August 15, 2009, prompt treatment with antiviral drugs was recommended when an infection was suspected. Free antiviral drugs were distributed to patients who met the case definition in the treatment guidelines, and patients prescribed the antiviral drugs were included in the Antiviral Drug Surveillance System (ADSS. A total of 2,825,821 patients were reported to the ADSS from September 1 to December 31, 2009. Odds ratios were calculated to compare the risks of severe diseases, as indicated by general hospital admissions or intensive care unit (ICU admissions according to demographic characteristics, underlying medical conditions, and behavioral factors. Approximately 6% of the total population received antiviral drugs during the study period. Of these, 2,709,611 (95.9% were outpatients, 114,840 (4.06% were hospitalized, and 1,370 (0.05% were admitted to the ICU. Children aged 0-9 yr accounted for 33.94% of all reported cases, whereas only 3.89% of the patients were ≥ 60 yr. The estimated incidence of novel influenza A (H1N1 during the pandemic was 5.68/100 of all reported cases. Mortality due to influenza A (H1N1 during the pandemic was 0.33/100,000, with the highest mortality of 1.31/100,000 for patients aged ≥ 60 years. Severe pandemic H1N1 influenza was associated with the presence of one or more underlying medical conditions in elderly aged ≥ 60 years and with lower economic status. Moreover, influenza A (H1N1 appeared to be age-specific in terms of mortality. Although the incidence and admission rates of influenza A (H1N1 were higher in younger age groups, fatal cases were much more likely to occur in the elderly (≥ 60 years. In contrast to earlier influenza A (H1N1 reports, the risks of a severe outcome were elevated among those who were underweight (body mass index < 18.5 kg/m(2.

  19. Advances in research and development of new drugs for antiviral therapy for chronic hepatitis B

    Directory of Open Access Journals (Sweden)

    GAO Yanhang

    2016-11-01

    Full Text Available Chronic hepatitis B virus (HBV infection is one of the major disease burdens worldwide. At present, the antiviral therapy for hepatitis B includes interferons and nucleos(tide analogues. Current therapeutic regimens based on these drugs cannot significantly increase the proportion of patients with functional cure. With a better understanding of HBV replication cycle and specific virus-host cell interactions, this article summarizes and reviews the advances in the research and development of new drugs for HBV with a focus on different action targets during the above processes.

  20. Oseltamivir and indomethacin reduce the oxidative stress in brain and stomach of infected rats.

    Science.gov (United States)

    Guzmán, David Calderón; Herrera, Maribel Ortiz; Brizuela, Norma Osnaya; Mejía, Gerardo Barragán; García, Ernestina Hernández; Olguín, Hugo Juárez; Ruíz, Norma Labra; Peraza, Armando Valenzuela

    2017-12-21

    The aim of this study was to determine the effect of oseltamivir and indomethacin on lipid peroxidation (LP), GABA levels, and ATPase activity in brain and stomach of normal and infected rats (IR), as novel inflammation model. Female Sprague Dawley rats grouped five each, either in the absence or presence of a live culture of Salmonella typhimurium (S. typh), were treated as follows: group 1 (control), PBS buffer; group 2, oseltamivir (100 mg/kg); group 3, indomethacin (67 μg/rat); group 4, oseltamivir (100 mg/kg) + indomethacin (67 μg/rat). All drugs were given intraperitoneally for 5 days. IR received the same treatments and the brain and stomach of the rats were removed in order to measure levels of GABA, LP, and total ATPase, using validated methods. Levels of GABA increased in stomach and cortex of IR with oseltamivir, but decreased in striatum and cerebellum/medulla oblongata of IR with indomethacin. LP decreased in the three brain regions of IR with oseltamivir. ATPase increased in stomach of IR and non-IR with oseltamivir and in striatum and cerebellum/medulla oblongata of IR with indomethacin. Results suggest that the effect of free radicals produced in an infection and inflammatory condition caused by S. typh could be less toxic by a combination of oseltamivir and indomethacin. © 2017 APMIS. Published by John Wiley & Sons Ltd.

  1. Immunological and pathogenic properties of poliovirus variants selected for resistance to antiviral drug V-073.

    Science.gov (United States)

    Kouiavskaia, Diana V; Dragunsky, Eugenia M; Liu, Hong-Mei; Oberste, M Steven; Collett, Marc S; Chumakov, Konstantin M

    2011-01-01

    The National Research Council has recommended development of polio antiviral drugs to assist in management of outbreaks and to mitigate adverse consequences of vaccination. V-073 is a small molecule poliovirus capsid inhibitor that is being developed for these purposes. Antiviral use raises the potential of treatment-emergent resistance. Understanding virological consequences of resistance is important. Six independent laboratory-derived V-073-resistant poliovirus variants were characterized for their ability to be neutralized by conventional vaccine-induced immune sera, to elicit serum neutralizing antibodies upon CD-1 mouse immunization, and to replicate in and to cause paralysis of TgPVR21 mice. V-073-resistant variants were effectively neutralized by oral poliovirus vaccine and inactivated poliovirus vaccine human immune sera. All variants elicited virus neutralizing antibody titres in CD-1 mice that were comparable to drug-susceptible parental and Sabin vaccine strain viruses. Infection efficiency of TgPVR21 mice by variants was comparable to (1 of 6 variants) or considerably lower than (5 of 6 variants) parental viruses. Drug-resistant variants replicated to levels comparable to (1 of 6 variants) or substantially less than (5 of 6 variants) their drug-susceptible parental viruses and were on average 1.4 log(10) (range 0.3 to >2.8 log₁₀) less neurovirulent. Laboratory-derived V-073-resistant variants exhibit clear attenuation of pathogenic properties while maintaining immunological features of drug-susceptible viruses.

  2. Letermovir and inhibitors of the terminase complex: a promising new class of investigational antiviral drugs against human cytomegalovirus

    Directory of Open Access Journals (Sweden)

    Melendez DP

    2015-08-01

    Full Text Available Dante P Melendez,1,2 Raymund R Razonable1,2 1Division of Infectious Diseases, 2William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, USA Abstract: Infection with cytomegalovirus is prevalent in immunosuppressed patients. In solid organ transplant and hematopoietic stem cell transplant recipients, cytomegalovirus infection is associated with high morbidity and preventable mortality. Prevention and treatment of cytomegalovirus with currently approved antiviral drugs is often associated with side effects that sometimes preclude their use. Moreover, cytomegalovirus has developed mutations that confer resistance to standard antiviral drugs. During the last decade, there have been calls to develop novel antiviral drugs that could provide better options for prevention and treatment of cytomegalovirus. Letermovir (AIC246 is a highly specific antiviral drug that is currently undergoing clinical development for the management of cytomegalovirus infection. It acts by inhibiting the viral terminase complex. Letermovir is highly potent in vitro and in vivo against cytomegalovirus. Because of a distinct mechanism of action, it does not exhibit cross-resistance with other antiviral drugs. It is predicted to be active against strains that are resistant to ganciclovir, foscarnet, and cidofovir. To date, early-phase clinical trials suggest a very low incidence of adverse effects. Herein, we present a comprehensive review on letermovir, from its postulated novel mechanism of action to the results of most recent clinical studies. Keywords: cytomegalovirus, letermovir, AIC246, terminase, antivirals, transplantation 

  3. Virus load kinetics and resistance development during oseltamivir treatment in infants and children infected with Influenza A(H1N1) 2009 and Influenza B viruses.

    Science.gov (United States)

    Rath, Barbara; von Kleist, Max; Tief, Franziska; Karsch, Katharina; Tuerk, Ewelina; Muehlhans, Susann; Louis, Florian; Skopnik, Heino; Schweiger, Brunhilde; Duwe, Susanne

    2012-09-01

    Infants and small children are the most effective transmitters of influenza, while bearing a high risk of hospitalization and adverse disease outcomes. This study aims to investigate virus load kinetics and resistance development during oseltamivir therapy in infants and children infected with influenza A(H1N1) 2009 and influenza B viruses. Virus load in nasopharyngeal samples and phenotypic/genotypic neuraminidase inhibitor resistance were determined at baseline, at day 5 and in additional follow-up samples, if available. Patient-specific viral clearance indices CLν(i) were determined along with estimates of the time required to achieve nondetectable virus load. No evidence of baseline oseltamivir resistance was detected in 36 patients infected with influenza A(H1N1) 2009 (n = 27) or influenza B (Victoria, Yamagata; n = 9) before oseltamivir therapy. On average, viral loads were lower for influenza type B (median = 5.9·10/mL) than for drug-resistant (median = 2.6·10/mL) and sensitive A(H1N1) 2009 (median = 4.8·10/mL), P = 0.04 and P = 0.09, respectively. Time required to achieve nondetectable virus load was significantly longer in drug-resistant A(H1N1) 2009 (median 15.4 days) compared with drug-sensitive A(H1N1) 2009 (P = 0.003; median 7.7 days) and drug-sensitive influenza B (P = 0.001; median 5 days). No evidence of viral rebound was observed once viral clearance was achieved. Our data indicate that influenza subtyping in combination with baseline viral load measurements might help to optimize the duration of antiviral therapy in the individual child. Lower than expected virologic response rates in patients without malabsorption or compliance issues may suggest resistance development.

  4. Effects of dexamethasone coadministered with oseltamivir on the pharmacokinetics of oseltamivir in healthy volunteers

    Directory of Open Access Journals (Sweden)

    Jang K

    2017-03-01

    Full Text Available Kyungho Jang,1,2,* Min-Kyoung Kim,3,4,* Jaeseong Oh,1 SeungHwan Lee,1 Joo-Youn Cho,1 Kyung-Sang Yu,1 Tai Kiu Choi,3 Sang-Hyuk Lee,3,4 Kyoung Soo Lim4 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 2Center for Clinical Pharmacology and Biomedical Research Institute, Chonbuk National University Medical School, Jeonju, 3Department of Psychiatry, 4Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and CHA Bundang Medical Center, Seongnam, Republic of Korea *These authors contributed equally to this work Purpose: Oseltamivir is widely used in the treatment and prophylaxis of influenza A and B viral infections. It is ingested as an oral prodrug that is rapidly metabolized by carboxylesterase 1 (CES1 to its active form, oseltamivir carboxylate. Dexamethasone is also used in the treatment of acute respiratory distress syndrome, a severe complication of influenza; however, its influence on the pharmacokinetics (PK of oseltamivir is controversial. The aim of this study was to investigate the effects of coadministering oseltamivir and dexamethasone on the PK of oseltamivir in healthy volunteers. Methods: An open-label, two-period, one-sequence, multiple-dose study was conducted in 19 healthy male volunteers. Oseltamivir (75 mg was orally administered on Day 1 and Day 8, and dexamethasone (1.5 mg was administered once daily from Day 3 to Day 8. Serial blood and urine samples were collected for PK analysis of oseltamivir and oseltamivir carboxylate on Day 1 and Day 8. Oseltamivir and oseltamivir carboxylate concentrations in plasma and urine were determined using liquid chromatography–tandem mass spectrometry. Results: Area under the plasma concentration–time curve (AUC of oseltamivir and oseltamivir carboxylate decreased after dexamethasone treatment for 6 days. The geometric mean ratio (90% confidence interval of the metabolic ratio

  5. Utility of humanized BLT mice for analysis of dengue virus infection and antiviral drug testing.

    Science.gov (United States)

    Frias-Staheli, Natalia; Dorner, Marcus; Marukian, Svetlana; Billerbeck, Eva; Labitt, Rachael N; Rice, Charles M; Ploss, Alexander

    2014-02-01

    Dengue virus (DENV) is the cause of a potentially life-threatening disease that affects millions of people worldwide. The lack of a small animal model that mimics the symptoms of DENV infection in humans has slowed the understanding of viral pathogenesis and the development of therapies and vaccines. Here, we investigated the use of humanized "bone marrow liver thymus" (BLT) mice as a model for immunological studies and assayed their applicability for preclinical testing of antiviral compounds. Human immune system (HIS) BLT-NOD/SCID mice were inoculated intravenously with a low-passage, clinical isolate of DENV-2, and this resulted in sustained viremia and infection of leukocytes in lymphoid and nonlymphoid organs. In addition, DENV infection increased serum cytokine levels and elicited DENV-2-neutralizing human IgM antibodies. Following restimulation with DENV-infected dendritic cells, in vivo-primed T cells became activated and acquired effector function. An adenosine nucleoside inhibitor of DENV decreased the circulating viral RNA when administered simultaneously or 2 days postinfection, simulating a potential treatment protocol for DENV infection in humans. In summary, we demonstrate that BLT mice are susceptible to infection with clinical DENV isolates, mount virus-specific adaptive immune responses, and respond to antiviral drug treatment. Although additional refinements to the model are required, BLT mice are a suitable platform to study aspects of DENV infection and pathogenesis and for preclinical testing of drug and vaccine candidates. IMPORTANCE Infection with dengue virus remains a major medical problem. Progress in our understanding of the disease and development of therapeutics has been hampered by the scarcity of small animal models. Here, we show that humanized mice, i.e., animals engrafted with components of a human immune system, that were infected with a patient-derived dengue virus strain developed clinical symptoms of the disease and mounted

  6. Influenza A(H1N1) oseltamivir resistant viruses in the Netherlands during the winter 2007/2008.

    NARCIS (Netherlands)

    Dijkstra, F.; Jonges, M.; Beek, R. van; Donker, G.A.; Schellevis, F.G.; Koopmans, M.; Sande, M.A.B. van der; Osterhaus, A.D.M.E.; Boucher, C.A.B.; Rimmelzwaan, G.F.; Meijer, A.

    2011-01-01

    Background: Antiviral susceptibility surveillance in the Netherlands was intensified after the first reports about the emergence of influenza A(H1N1) oseltamivir resistant viruses in Norway in January, 2008. Methods: Within the existing influenza surveillance an additional questionnaire study was

  7. Hepatitis B virus reverse transcriptase - Target of current antiviral therapy and future drug development.

    Science.gov (United States)

    Clark, Daniel N; Hu, Jianming

    2015-11-01

    Hepatitis B virus (HBV) infections rely on the proper functioning of the viral polymerase enzyme, a specialized reverse transcriptase (RT) with multiple activities. All currently approved antiviral drugs for the treatment of chronic HBV infection, except for interferon, target the RT and belong to the same chemical class - they are all nucleoside analogs. Viral DNA synthesis is carried out by the RT enzyme in several different steps, each with distinct RT conformational requirements. In principle, each stage may be targeted by distinct antiviral drugs. In particular, the HBV RT has the unique ability to initiate viral DNA synthesis using itself as a protein primer in a novel protein priming reaction. In order to help identify RT inhibitors and study their mechanisms of action, a number of experimental systems have been developed, each varying in its ability to dissect the protein priming stage and subsequent stages of viral DNA synthesis at the molecular level. Two of the most effective drugs to date, entecavir and tenofovir, can inhibit both the protein priming and the subsequent DNA elongation stages of HBV DNA synthesis. Interestingly, clevudine, a thymidine analog, can inhibit both protein priming and DNA elongation in a non-competitive manner and without being incorporated into the viral DNA. Thus, a nucleoside RT inhibitor (NRTI) can functionally mimic a non-NRTI (NNRTI) in its inhibition of the HBV RT. Therefore, novel NRTIs as well as NNRTIs may be developed to inhibit the DNA synthesis activity of the HBV RT. Furthermore, additional activities of the RT that are also essential to HBV replication, including specific recognition of the viral RNA and its packaging into viral nucleocapsids, may be exploited for antiviral development. To achieve a more potent inhibition of viral replication and ultimately cure chronic HBV infection, the next generation of anti-HBV therapies will likely need to include NRTIs, NNRTIs, and other agents that target the viral RT as

  8. Utility of Humanized BLT Mice for Analysis of Dengue Virus Infection and Antiviral Drug Testing

    Science.gov (United States)

    Frias-Staheli, Natalia; Dorner, Marcus; Marukian, Svetlana; Billerbeck, Eva; Labitt, Rachael N.; Rice, Charles M.

    2014-01-01

    ABSTRACT Dengue virus (DENV) is the cause of a potentially life-threatening disease that affects millions of people worldwide. The lack of a small animal model that mimics the symptoms of DENV infection in humans has slowed the understanding of viral pathogenesis and the development of therapies and vaccines. Here, we investigated the use of humanized “bone marrow liver thymus” (BLT) mice as a model for immunological studies and assayed their applicability for preclinical testing of antiviral compounds. Human immune system (HIS) BLT-NOD/SCID mice were inoculated intravenously with a low-passage, clinical isolate of DENV-2, and this resulted in sustained viremia and infection of leukocytes in lymphoid and nonlymphoid organs. In addition, DENV infection increased serum cytokine levels and elicited DENV-2-neutralizing human IgM antibodies. Following restimulation with DENV-infected dendritic cells, in vivo-primed T cells became activated and acquired effector function. An adenosine nucleoside inhibitor of DENV decreased the circulating viral RNA when administered simultaneously or 2 days postinfection, simulating a potential treatment protocol for DENV infection in humans. In summary, we demonstrate that BLT mice are susceptible to infection with clinical DENV isolates, mount virus-specific adaptive immune responses, and respond to antiviral drug treatment. Although additional refinements to the model are required, BLT mice are a suitable platform to study aspects of DENV infection and pathogenesis and for preclinical testing of drug and vaccine candidates. IMPORTANCE PMID:24335303

  9. Drug-class specific impact of antivirals on the reproductive capacity of HIV.

    Directory of Open Access Journals (Sweden)

    Max von Kleist

    2010-03-01

    Full Text Available Predictive markers linking drug efficacy to clinical outcome are a key component in the drug discovery and development process. In HIV infection, two different measures, viral load decay and phenotypic assays, are used to assess drug efficacy in vivo and in vitro. For the newly introduced class of integrase inhibitors, a huge discrepancy between these two measures of efficacy was observed. Hence, a thorough understanding of the relation between these two measures of drug efficacy is imperative for guiding future drug discovery and development activities in HIV. In this article, we developed a novel viral dynamics model, which allows for a mechanistic integration of the mode of action of all approved drugs and drugs in late clinical trials. Subsequently, we established a link between in vivo and in vitro measures of drug efficacy, and extract important determinants of drug efficacy in vivo. The analysis is based on a new quantity-the reproductive capacity-that represents in mathematical terms the in vivo analog of the read-out of a phenotypic assay. Our results suggest a drug-class specific impact of antivirals on the total amount of viral replication. Moreover, we showed that the (drug-target half life, dominated by immune-system related clearance processes, is a key characteristic that affects both the emergence of resistance as well as the in vitro-in vivo correlation of efficacy measures in HIV treatment. We found that protease- and maturation inhibitors, due to their target half-life, decrease the total amount of viral replication and the emergence of resistance most efficiently.

  10. A method for evaluating antiviral drug susceptibility of Epstein-Barr virus

    Directory of Open Access Journals (Sweden)

    Charlotte A Romain

    2010-01-01

    Full Text Available Charlotte A Romain1, Henry H Balfour Jr1,2, Heather E Vezina1,3, Carol J Holman11Department of Laboratory Medicine and Pathology, 2Department of Pediatrics, 3Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USAAbstract: We developed an in vitro Epstein-Barr virus (EBV drug susceptibility assay using P3HR1 cells or lymphoblastoid cells from subjects with infectious mononucleosis, which were grown in the presence of various concentrations of acyclovir (ACV, ganciclovir (GCV or R-9-[4-hydroxy-2-(hydroxymethylbutyl]guanine (H2G and 12-O-tetradecanoyl-phorbol-13-acetate (TPA. On day 7, total cellular DNA was extracted and EBV DNA was detected using an in-house quantitative real-time polymerase chain reaction (PCR method. All three drugs had in vitro activity against EBV in both the laboratory standard producer cell line P3HR1 and in subject-derived lymphoblastoid cell lines. The median 50% inhibitory concentrations (IC50s in P3HR1 cells were: ACV, 3.4 μM; GCV, 2.6 μM; and H2G, 2.7 μM and in 3 subject-derived cells were: ACV, 2.5 μM; GCV, 1.7 μM; and H2G, 1.9 μM. Our assay can be used to screen candidate anti-EBV drugs. Because we can measure the IC50 of patients’ strains of EBV, this assay may also be useful for monitoring viral resistance especially in immunocompomised hosts receiving antiviral drugs for prevention or treatment of EBV diseases.Keywords: Epstein-Barr virus, ganciclovir, acyclovir, valomaciclovir, H2G, antivirals

  11. New Approaches for Quantitating the Inhibition of HIV-1 Replication by Antiviral Drugs in vitro and in vivo

    Science.gov (United States)

    McMahon, Moira A.; Shen, Lin; Siliciano, Robert F.

    2014-01-01

    Purpose of review With highly active anti-retroviral therapy (HAART), HIV-1 infection has become a manageable lifelong disease. Developing optimal treatment regimens requires understanding how to best measure anti-HIV activity in vitro and how drug dose response curves generated in vitro correlate with in vivo efficacy. Recent findings Several recent studies have indicated that conventional multi-round infectivity assays are inferior to single cycle assays at both low and high levels of inhibition. Multi-round infectivity assays can fail to detect subtle but clinically significant anti-HIV activity. The discoveries of the anti-HIV activity of the hepatitis B drug entecavir and the herpes simplex drug acyclovir were facilitated by single round infectivity assays. Recent studies using a single round infectivity assay have shown that a previously neglected parameter, the dose response curve slope, is an extremely important determinant of antiviral activity. Some antiretroviral drugs have steep slopes that result in extraordinary levels of antiviral activity. The instantaneous inhibitory potential (IIP), the log reduction in infectivity in a single round assay at clinical drug concentrations, has been proposed as a novel index for comparing antiviral activity. Summary Among in vitro measures of antiviral activity, single round infection assays have the advantage of measure instantaneous inhibition by a drug. Re-evaluating the antiviral activity of approved HIV-1 drugs has shown that the slope parameter is an important factor in drug activity. Determining the IIP by using a single round infectivity assay may provide important insights that can predict the in vivo efficacy of anti-HIV-1 drugs. PMID:19841584

  12. Assessment of Antiviral Properties of Peramivir against H7N9 Avian Influenza Virus in an Experimental Mouse Model.

    Science.gov (United States)

    Farooqui, Amber; Huang, Linxi; Wu, Suwu; Cai, Yingmu; Su, Min; Lin, Pengzhou; Chen, Weihong; Fang, Xibin; Zhang, Li; Liu, Yisu; Zeng, Tiansheng; Paquette, Stephane G; Khan, Adnan; Kelvin, Alyson A; Kelvin, David J

    2015-12-01

    The H7N9 influenza virus causes a severe form of disease in humans. Neuraminidase inhibitors, including oral oseltamivir and injectable peramivir, are the first choices of antiviral treatment for such cases; however, the clinical efficacy of these drugs is questionable. Animal experimental models are essential for understanding the viral replication kinetics under the selective pressure of antiviral agents. This study demonstrates the antiviral activity of peramivir in a mouse model of H7N9 avian influenza virus infection. The data show that repeated administration of peramivir at 30 mg/kg of body weight successfully eradicated the virus from the respiratory tract and extrapulmonary tissues during the acute response, prevented clinical signs of the disease, including neuropathy, and eventually protected mice against lethal H7N9 influenza virus infection. Early treatment with peramivir was found to be associated with better disease outcomes. Copyright © 2015 Farooqui et al.

  13. Simple fluorimetric method for determination of certain antiviral drugs via their oxidation with cerium (IV).

    Science.gov (United States)

    Darwish, Ibrahim A; Khedr, Alaa S; Askal, Hassan F; Mahmoud, Ramadan M

    2005-01-01

    A simple and sensitive fluorimetric method for determination of antiviral drugs: ribavirin, acyclovir, and amantadine hydrochloride has been developed. The method was based on the oxidation of these drugs by cerium(IV) in presence of perchloric acid and subsequent monitoring the fluorescence of the induced cerium(III) at lambdaexcitation 255 and lambdaemission 355 nm. Different variables affecting the reaction conditions such as the concentrations of cerium(IV), type and concentration of acid medium, reaction time, temperature, and the diluting solvents were carefully studied and optimized. Under the optimum conditions, linear relationships with good correlation coefficients (0.9978-0.9996) were found between the relative fluorescence intensity and the concentrations of the investigated drugs in the range of 50-1400 ng ml-1. The assay limits of detection and quantitation were 20-49, and 62-160 ng ml-1, respectively. The precision of the method was satisfactory; the values of relative standard deviations did not exceed 1.58%. No interference could be observed from the excipients commonly present in dosage forms. The proposed method was successfully applied to the analysis of the investigated drugs in pure and pharmaceutical dosage forms with good accuracy and precision; the recovery percentages ranged from 99.2 to 101.2+/-0.48-1.30%. The results obtained by the proposed fluorimetric method were comparable with those obtained by the official method stated in the United States Pharmacopoeia.

  14. Antiviral Drug-Resistant Influenza B Viruses Carrying H134N Substitution in Neuraminidase, Laos, February 2016.

    Science.gov (United States)

    Baranovich, Tatiana; Vongphrachanh, Phengta; Ketmayoon, Pakapak; Sisouk, Thongchanh; Chomlasack, Khampheng; Khanthamaly, Viengphone; Nguyen, Ha Thuy; Mishin, Vasiliy P; Marjuki, Henju; Barnes, John R; Garten, Rebecca J; Stevens, James; Wentworth, David E; Gubareva, Larisa V

    2017-04-01

    In February 2016, three influenza B/Victoria/2/87 lineage viruses exhibiting 4- to 158-fold reduced inhibition by neuraminidase inhibitors were detected in Laos. These viruses had an H134N substitution in the neuraminidase and replicated efficiently in vitro and in ferrets. Current antiviral drugs may be ineffective in controlling infections caused by viruses harboring this mutation.

  15. Restrictions for reimbursement of interferon-free direct-acting antiviral drugs for HCV infection in Europe

    NARCIS (Netherlands)

    Marshall, Alison D.; Cunningham, Evan B.; Nielsen, Stine; Aghemo, Alessio; Alho, Hannu; Backmund, Markus; Bruggmann, Philip; Dalgard, Olav; Seguin-Devaux, Carole; Flisiak, Robert; Foster, Graham R.; Gheorghe, Liana; Goldberg, David; Goulis, Ioannis; Hickman, Matthew; Hoffmann, Patrick; Jancorienė, Ligita; Jarcuska, Peter; Kåberg, Martin; Kostrikis, Leondios G.; Makara, Mihály; Maimets, Matti; Marinho, Rui Tato; Matičič, Mojca; Norris, Suzanne; Ólafsson, Sigurður; Øvrehus, Anne; Pawlotsky, Jean-Michel; Pocock, James; Robaeys, Geert; Roncero, Carlos; Simonova, Marieta; Sperl, Jan; Tait, Michele; Tolmane, Ieva; Tomaselli, Stefan; van der Valk, Marc; Vince, Adriana; Dore, Gregory J.; Lazarus, Jeffrey V.; Grebely, Jason

    2018-01-01

    All-oral direct-acting antiviral drugs (DAAs) for hepatitis C virus, which have response rates of 95% or more, represent a major clinical advance. However, the high list price of DAAs has led many governments to restrict their reimbursement. We reviewed the availability of, and national criteria

  16. Modified human serum albumins as carriers for the specific delivery of antiviral drugs to liver- and blood cells

    NARCIS (Netherlands)

    Jansen, Robert Walter

    1992-01-01

    The general goal of this study, was to determine the possibility of a targeted delivery of antiviral drugs to their site of action. We decided to focus on two viral diseases; HIV and Hepatitis B, that replicate in T,-lymphocytes, monocytes/macrophages and hepatocytes respectively. The specific aims

  17. Synthesis and Antiviral Evaluation of 6-(Trifluoromethylbenzyl) and 6-(Fluorobenzyl) Analogues of HIV Drugs Emivirine and GCA-186

    DEFF Research Database (Denmark)

    El-Brollosy, Nasser R.; Sørensen, Esben R.; Pedersen, Erik Bjerreg.

    2008-01-01

    The present study describes the synthesis and antiviral evaluation of a series of novel 6-(3-trifluoromethylbenzyl) and 6-(fluorobenzyl) analogues of the HIV drugs emivirine and GCA-186. The objective was to investigate whether the fluoro or trifluoromethyl substituents could lead to an improved ...

  18. Oseltamivir compounding in the hospital pharmacy during the (H1N1 influenza pandemic

    Directory of Open Access Journals (Sweden)

    Márcia Lúcia de Mário Marin

    2010-01-01

    Full Text Available AIMS: Pandemics impose large demands on the health care system. The supply of appropriate chemotherapeutic agents, namely oseltamivir solution, presented a serious challenge in the recent influenza pandemic. This study reports on the rational series of pharmacotechnical steps that were followed to appropriately handle bulk oseltamivir powder to meet the increased demand. METHODS: During a six-week period in August and September of 2009, a task force was created in the Central Pharmacy of Hospital das Clínicas to convert imported oseltamivir phosphate into ready-to-use solution for utilization by physicians and public health authorities. The protocol included dissolution, physico-chemical tests and the bottling of a liquid microdose formulation for emergency room and outpatient dispensing with adequate quality control during all phases. RESULTS: The successful production routine was based on a specially designed flowchart according to which a batch of 33210 g of oseltamivir powder was converted into 32175 solution units during the aforementioned period with a net loss of only 2.6%. The end products were bottles containing 50 ml of 15 mg/mL oseltamivir solution. The measured concentration was stable and accurate (97.5% - 102.0% of the nominal value. The drug was prescribed as both a prophylactic and therapeutic agent. DISCUSSION: Hospital pharmacies are conventionally engaged in the manipulation of medical prescriptions and specialty drugs. They are generally responsible for only small-scale equipment used for manufacturing and quality-control procedures. The compounding of oseltamivir was a unique effort dictated by exceptional circumstances. CONCLUSION: The shortage of oseltamivir solution for clinical use was solved by emergency operationalization of a semi-industrial process in which bulk powder was converted into practical vials for prompt delivery.

  19. Design and evaluation of novel interferon lambda analogs with enhanced antiviral activity and improved drug attributes

    Directory of Open Access Journals (Sweden)

    Yu D

    2016-01-01

    Full Text Available Debin Yu,1 Mingzhi Zhao,2 Liwei Dong,1 Lu Zhao,1 Mingwei Zou,3 Hetong Sun,4 Mengying Zhang,4 Hongyu Liu,4 Zhihua Zou1 1National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun, 2State Key Laboratory of Proteomics, National Engineering Research Center for Protein Drugs, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, People’s Republic of China; 3Department of Psychology, College of Liberal Arts and Social Sciences, University of Houston, Houston, TX, USA; 4Prosit Sole Biotechnology, Co., Ltd., Beijing, People’s Republic of China Abstract: Type III interferons (IFNs (also called IFN-λ: IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4 are critical players in the defense against viral infection of mucosal epithelial cells, where the activity of type I IFNs is weak, and unlike type I IFNs that are associated with severe and diverse side effects, type III IFNs cause minimal side effects due to the highly restricted expression of their receptors, and thus appear to be promising agents for the treatment and prevention of respiratory and gastrointestinal viral infection. However, the antiviral potency of natural type III IFNs is weak compared to type I and, although IFN-λ3 possesses the highest bioactivity among the type III IFNs, IFN-λ1, instead of IFN-λ3, is being developed as a therapeutic drug due to the difficulty to express IFN-λ3 in the prokaryotic expression system. Here, to develop optimal IFN-λ molecules with improved drug attributes, we designed a series of IFN-λ analogs by replacing critical amino acids of IFN-λ1 with the IFN-λ3 counterparts, and vice versa. Four of the designed analogs were successfully expressed in Escherichia coli with high yield and were easily purified from inclusion bodies. Interestingly, all four analogs showed potent activity in inducing the

  20. Boosting immunity by antiviral drug therapy: A simple relationship among timing, efficacy, and success

    Science.gov (United States)

    Komarova, Natalia L.; Barnes, Eleanor; Klenerman, Paul; Wodarz, Dominik

    2003-02-01

    Drug therapies against persistent human infections such as hepatitis C virus, hepatitis B virus, and HIV fail to consistently eradicate the infection from the host. Hence, recent emphasis has shifted to the study of antiviral therapy aimed at boosting specific immune responses. It was argued that structured therapy interruptions were required to achieve this, because such regimes have shown promising results in early HIV infection. Using mathematical models, we show that, contrary to this notion, a single phase of drug therapy can result in the establishment of sustained immunity. We present a simple relationship between timing of therapy and efficacy of the drugs required for success. In the presence of strong viral suppression, we show that therapy should be stopped relatively early, and that a longer duration of treatment leads to failure. On the other hand, in the presence of weaker viral suppression, stopping treatment too early is detrimental, and therapy has to be continued beyond a time threshold. We discuss our modeling results primarily in the context of HCV therapy during chronic infection. Although the therapy regimes explored here also have implications for HIV, virus-mediated destruction of specific immune cells renders success unlikely during the chronic phase of the infection.

  1. Diagnostic imaging of herpes simplex virus encephalitis using a radiolabeled antiviral drug: autoradiographic assessment in an animal model

    International Nuclear Information System (INIS)

    Saito, Y.; Rubenstein, R.; Price, R.W.; Fox, J.J.; Watanabe, K.A.

    1984-01-01

    To develop a new approach to the diagnosis of herpes simplex encephalitis, we used a radiolabeled antiviral drug, 2'-fluoro-5-methyl-1-beta-D-arabinosyluracil labeled with carbon 14 ([14C]FMAU), as a probe for selectively imaging brain infection in a rat model by quantitative autoradiography. A high correlation was found between focal infection, as defined by immunoperoxidase viral antigen staining, and increased regional [14C]FMAU uptake in brain sections. Two potential sources of false-positive imaging were defined: high concentrations of drug in the choroid plexus because of its higher permeability compared with brain, and drug sequestration by proliferating uninfected cell populations. Our results support the soundness of the proposed strategy of using a labeled antiviral drug that is selectively phosphorylated by herpes simplex virus type 1 thymidine kinase in conjunction with scanning methods for human diagnosis, and also define some of the factors that must be taken into account when planning clinical application

  2. Oseltamivir

    Science.gov (United States)

    ... regular or sugar-free chocolate syrup, corn syrup, caramel topping, or light brown sugar dissolved in water ... weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and ...

  3. Nanomedicine formulations for the delivery of antiviral drugs: a promising solution for the treatment of viral infections.

    Science.gov (United States)

    Lembo, David; Donalisio, Manuela; Civra, Andrea; Argenziano, Monica; Cavalli, Roberta

    2018-01-01

    Viral infections represent a public health problem and one of the leading causes of global mortality. Nanomedicine strategies can be considered a powerful tool to enhance the effectiveness of antiviral drugs, often associated with solubility and bioavailability issues. Consequently, high doses and frequent administrations are required, resulting in adverse side effects. To overcome these limitations, various nanomedicine platforms have been designed. Areas covered: This review focuses on the state of the art of organic-based nanoparticles for the delivery of approved antivirals. A brief description of the main characteristics of nanocarriers is followed by an overview of the most promising research addressing the treatment of most important viral infections. Expert opinion: The activity of antiviral drugs could be improved with nanomedicine formulations. Indeed, nanoparticles can affect the fate of the encapsulated drugs, allowing controlled release kinetics, enhanced bioavailability, modified pharmacokinetics, and reduced side effects. In addition, the physicochemical properties of nanocarriers can enable their capability to target specific sites and to interact with virus structures. In this regard, nanomedicines can be considered an opportunity to enhance the therapeutic index of antivirals. Efficacy, safety, and manufacturing issues need to be carefully assessed to bring this promising approach to the clinic.

  4. Thieno[2,3-b]pyridine derivatives: a new class of antiviral drugs against Mayaro virus.

    Science.gov (United States)

    Amorim, Raquel; de Meneses, Marcelo Damião Ferreira; Borges, Julio Cesar; da Silva Pinheiro, Luiz Carlos; Caldas, Lucio Ayres; Cirne-Santos, Claudio Cesar; de Mello, Marcos Vinícius Palmeira; de Souza, Alessandra Mendonça Teles; Castro, Helena Carla; de Palmer Paixão, Izabel Christina Nunes; Campos, Renata de Mendonça; Bergmann, Ingrid E; Malirat, Viviana; Bernardino, Alice Maria Rolim; Rebello, Moacyr Alcoforado; Ferreira, Davis Fernandes

    2017-06-01

    Mayaro virus (MAYV) is an arthropod-borne virus and a member of the family Togaviridae, genus Alphavirus. Its infection leads to an acute illness accompanied by long-lasting arthralgia. To date, there are no antiviral drugs or vaccines against infection with MAYV and resources for the prevention or treatment of other alphaviruses are very limited. MAYV has served as a model to study the antiviral potential of several substances on alphavirus replication. In this work we evaluated the antiviral effect of seven new derivatives of thieno[2,3-b]pyridine against MAYV replication in a mammalian cell line. All derivatives were able to reduce viral production effectively at concentrations that were non-toxic for Vero cells. Molecular modeling assays predicted low toxicity risk and good oral bioavailability of the substances in humans. One of the molecules, selected for further study, demonstrated a strong anti-MAYV effect at early stages of replication, as it protected pre-treated cells and also during the late stages, affecting virus morphogenesis. This study is the first to demonstrate the antiviral effect of thienopyridine derivatives on MAYV replication in vitro, suggesting the potential application of these substances as antiviral molecules against alphaviruses. Additional in vivo research will be needed to expand the putative therapeutic applications.

  5. Systems Biology-Based Investigation of Cellular Antiviral Drug Targets Identified by Gene-Trap Insertional Mutagenesis.

    Directory of Open Access Journals (Sweden)

    Feixiong Cheng

    2016-09-01

    Full Text Available Viruses require host cellular factors for successful replication. A comprehensive systems-level investigation of the virus-host interactome is critical for understanding the roles of host factors with the end goal of discovering new druggable antiviral targets. Gene-trap insertional mutagenesis is a high-throughput forward genetics approach to randomly disrupt (trap host genes and discover host genes that are essential for viral replication, but not for host cell survival. In this study, we used libraries of randomly mutagenized cells to discover cellular genes that are essential for the replication of 10 distinct cytotoxic mammalian viruses, 1 gram-negative bacterium, and 5 toxins. We herein reported 712 candidate cellular genes, characterizing distinct topological network and evolutionary signatures, and occupying central hubs in the human interactome. Cell cycle phase-specific network analysis showed that host cell cycle programs played critical roles during viral replication (e.g. MYC and TAF4 regulating G0/1 phase. Moreover, the viral perturbation of host cellular networks reflected disease etiology in that host genes (e.g. CTCF, RHOA, and CDKN1B identified were frequently essential and significantly associated with Mendelian and orphan diseases, or somatic mutations in cancer. Computational drug repositioning framework via incorporating drug-gene signatures from the Connectivity Map into the virus-host interactome identified 110 putative druggable antiviral targets and prioritized several existing drugs (e.g. ajmaline that may be potential for antiviral indication (e.g. anti-Ebola. In summary, this work provides a powerful methodology with a tight integration of gene-trap insertional mutagenesis testing and systems biology to identify new antiviral targets and drugs for the development of broadly acting and targeted clinical antiviral therapeutics.

  6. Oseltamivir Prophylaxis Reduces Inflammation and Facilitates Establishment of Cross-Strain Protective T Cell Memory to Influenza Viruses

    OpenAIRE

    Bird, Nicola L.; Olson, Matthew R.; Hurt, Aeron C.; Oshansky, Christine M.; Oh, Ding Yuan; Reading, Patrick C.; Chua, Brendon Y.; Sun, Yilun; Tang, Li; Handel, Andreas; Jackson, David C.; Turner, Stephen J.; Thomas, Paul G.; Kedzierska, Katherine

    2015-01-01

    CD8(+) T cells directed against conserved viral regions elicit broad immunity against distinct influenza viruses, promote rapid virus elimination and enhanced host recovery. The influenza neuraminidase inhibitor, oseltamivir, is prescribed for therapy and prophylaxis, although it remains unclear how the drug impacts disease severity and establishment of effector and memory CD8(+) T cell immunity. We dissected the effects of oseltamivir on viral replication, inflammation, acute CD8(+) T cell r...

  7. High frequency of antiviral drug resistance and non-b subtypes in HIV-1 patients failing antiviral therapy in Cuba.

    Science.gov (United States)

    Kouri, Vivian; Alemán, Yoan; Pérez, Lissette; Pérez, Jorge; Fonseca, Carlos; Correa, Consuelo; Aragonés, Carlos; Campos, Jorge; Alvarez, Delmis; Schrooten, Yoeri; Vinken, Lore; Limia, Celia; Soto, Yudira; Vandamme, Anne-Mieke; Van Laethem, Kristel

    2014-01-01

    Emergence of HIV-1 drug resistance may limit the sustained benefits of antiretroviral therapy (ART) in settings with limited laboratory monitoring and drug options. The objective is to implement the surveillance of drug resistance and subtypes in HIV-1 patients failing ART in Cuba. This study compiled clinical and genotypic drug resistance data 588 ART-experienced HIV-1 patients attending a clinical center in Havana in 2009-2013. Drug resistance testing was performed as part of routine clinical care. Drug resistance mutations and levels were determined using Rega version 8.0.2. Eighty-three percent received solely ART containing at least three drugs. Patients from 2009 to 2010 were longer treated (median: 4.9 vs 2.7 years) and exposed to more ART regimens (median: 4 vs 2 regimens) compared to patients from 2011-2013. Nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside RTI (NNRTI) and PI mutations were present in 83.5, 77.4 and 52.0%. Full-class resistance (FCR) to NRTI, NNRTI, PI and multidrug resistance (MDR) were detected in 25.0, 33.7, 11.4 and 6.3%. FCR to NRTI, NNRTI, PI and MDR were present in 12.8, 28.7, 0 and 0% after first-line failure (164 patients) and in 23.1, 34.6, 3.8 and 3.1% after second-line failure (130 patients). Subtype B (32.5%), BG recombinants (19.6%) and CRF19_cpx (16.2%) were the most prevalent genetic forms. Subtype distribution did not change significantly between 2009-2010 and 2011-2013, except for BG recombinants that increased from 12.2 to 21.3% (p=0.002). Our study found a high prevalence of drug resistance and supports the need for appropriate laboratory monitoring in clinical practice and access to drug options in case of virological failure.

  8. Molecular Characterization of Three Porcine Reproductive and Respiratory Syndrome Virus Isolates and Their Susceptibility to Antiviral Drugs

    Directory of Open Access Journals (Sweden)

    Hongxia Hu

    2014-01-01

    Full Text Available Porcine reproductive and respiratory syndrome virus (PRRSV is one of the most common swine pathogens that cause severe economic losses to the pig industry worldwide irrespective of the use of live or inactivated vaccines. This study aims to investigate the biological characteristics of three PRRSV isolates and their susceptibility to two antiviral drugs. Sequence analysis of the NSP2 gene classified two isolates as highly pathogenic (isolates FY and ZS and one as classically pathogenic (isolate JX. Isolate FY grew faster than the other two isolates in MARC-145 cells; however, its RNA replication was lower than isolate ZS. By contrast, isolate JX exhibited slower growth and lower RNA replication capability. PRRSV infection suppressed the production of interferon β induced by poly (I:C. The viruses also differed in their susceptibility to antiviral drugs. Ribavirin exerted potent antiviral activity against all three viral isolates at concentrations of 7.5 and 15 μg/mL in MARC-145 cells. Acyclovir was found effective only on the classically pathogenic isolate. We suggest that ribavirin could have potential as an antiviral therapy for porcine reproductive and respiratory syndrome when vaccination is not able to provide effective protection.

  9. A Critical Subset Model Provides a Conceptual Basis for the High Antiviral Activity of Major HIV Drugs**

    Science.gov (United States)

    Shen, Lin; Rabi, S. Alireza; Sedaghat, Ahmad R.; Shan, Liang; Lai, Jun; Xing, Sifei; Siliciano, Robert F.

    2012-01-01

    Control of HIV-1 replication was first achieved with regimens that included a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI); however, an explanation for the high antiviral activity of these drugs has been lacking. Indeed, conventional pharmacodynamic measures like IC50 (drug concentration causing 50% inhibition) do not differentiate NNRTIs and PIs from less active nucleoside reverse transcriptase inhibitors (NRTIs). Drug inhibitory potential depends on the slope of the dose-response curve (m), which represents how inhibition increases as a function of increasing drug concentration and is related to the Hill coefficient, a measure of intramolecular cooperativity in ligand binding to a multivalent receptor. Although NNRTIs and PIs bind univalent targets, they unexpectedly exhibit cooperative dose-response curves (m > 1). We show that this cooperative inhibition can be explained by a model in which infectivity requires participation of multiple copies of a drug target in an individual life cycle stage. A critical subset of these target molecules must be in the unbound state. Consistent with experimental observations, this model predicts m > 1 for NNRTIs and PIs and m = 1 in situations where a single drug target/virus mediates a step in the life cycle, as is the case with NRTIs and integrase strand transfer inhibitors. This model was tested experimentally by modulating the number of functional drug targets per virus, and dose-response curves for modulated virus populations fit model predictions. This model explains the high antiviral activity of two drug classes important for successful HIV-1 treatment and defines a characteristic of good targets for antiviral drugs in general, namely, intermolecular cooperativity. PMID:21753122

  10. Oseltamivir Prophylaxis Reduces Inflammation and Facilitates Establishment of Cross-Strain Protective T Cell Memory to Influenza Viruses.

    Directory of Open Access Journals (Sweden)

    Nicola L Bird

    Full Text Available CD8(+ T cells directed against conserved viral regions elicit broad immunity against distinct influenza viruses, promote rapid virus elimination and enhanced host recovery. The influenza neuraminidase inhibitor, oseltamivir, is prescribed for therapy and prophylaxis, although it remains unclear how the drug impacts disease severity and establishment of effector and memory CD8(+ T cell immunity. We dissected the effects of oseltamivir on viral replication, inflammation, acute CD8(+ T cell responses and the establishment of immunological CD8(+ T cell memory. In mice, ferrets and humans, the effect of osteltamivir on viral titre was relatively modest. However, prophylactic oseltamivir treatment in mice markedly reduced morbidity, innate responses, inflammation and, ultimately, the magnitude of effector CD8(+ T cell responses. Importantly, functional memory CD8(+ T cells established during the drug-reduced effector phase were capable of mounting robust recall responses. Moreover, influenza-specific memory CD4(+ T cells could be also recalled after the secondary challenge, while the antibody levels were unaffected. This provides evidence that long-term memory T cells can be generated during an oseltamivir-interrupted infection. The anti-inflammatory effect of oseltamivir was verified in H1N1-infected patients. Thus, in the case of an unpredicted influenza pandemic, while prophylactic oseltamivir treatment can reduce disease severity, the capacity to generate memory CD8(+ T cells specific for the newly emerged virus is uncompromised. This could prove especially important for any new influenza pandemic which often occurs in separate waves.

  11. Nanoscale determination of antiviral drug acyclovir engaging bifunctionality of single walled carbon nanotubes - nafion film.

    Science.gov (United States)

    Tarlekar, Pravin; Khan, Afsan; Chatterjee, Sanghamitra

    2018-03-20

    An elementary and exemplary approach is proposed for the accurate monitoring of antiviral drug acyclovir (ACV) utilizing glassy carbon electrode (GCE) fabricated with single-walled carbon nanotubes and nafion composite film employing square wave voltammetry for the first time. The developed sensor exhibits effective and sustained electron mediating behavior displaying higher peak currents at lower potential than those obtained at bare GCE. At optimal experimental conditions, oxidation current showed a wide linear response for ACV in the concentration range from 10 nM to 30 μM. The proposed sensor exhibited pronounced analytical performance for the determination of ACV with limit of detection corresponding to 1.8 nM and high sensitivity of 15.4 μA μM -1 . The modified sensor showcased high recognition selectivity, fair reproducibility and long term stability of signal response in the physiological environment. The developed prototype was successfully implemented to quantify ACV in several commercially available pharmaceuticals. The versatile method described herein was efficaciously applied further in detecting ACV in real human urine sample of patient undergoing pharmacological treatment with ACV. The results explicitly demonstrate the applicability of the developed sensor in quality control, pharmacokinetic studies and clinical analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Designing cyclopentapeptide inhibitor as potential antiviral drug for dengue virus ns5 methyltransferase.

    Science.gov (United States)

    Idrus, Syarifuddin; Tambunan, Usman Sumo Friend; Zubaidi, Ahmad Ardilla

    2012-01-01

    NS5 methyltransferase (Mtase) has a crucial role in the replication of dengue virus. There are two active sites on NS5 Mtase i.e., SAM and RNA-cap binding sites. Inhibition of the NS5 Mtase activity is expected to prevent the propagation of dengue virus. This study was conducted to design cyclic peptide ligands as enzyme inhibitors of dengue virus NS5 Mtase through computational approach. Cyclopentapeptides were designed as ligand of SAM binding site as much as 1635 and 736 cyclopentpeptides were designed as ligand of RNA-cap binding site. Interaction between ligand and NS5 Mtase has been conducted on the Docking simulation. The result shows that cyclopentapeptide CTWYC was the best peptide candidate on SAM binding site, with estimated free binding energy -30.72 kca/mol. Cyclopentapeptide CYEFC was the best peptide on RNA-cap binding site with estimated free binding energy -22.89 kcal/mol. Both peptides did not have tendency toward toxicity properties. So it is expected that both CTWYC and CYEFC ligands could be used as a potential antiviral drug candidates, which can inhibit the SAM and RNA-cap binding sites of dengue virus NS5 Mtase.

  13. Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

    Energy Technology Data Exchange (ETDEWEB)

    Kadam, Rameshwar U.; Wilson, Ian A.

    2016-12-21

    The broad-spectrum antiviral drug Arbidol shows efficacy against influenza viruses by targeting the hemagglutinin (HA) fusion machinery. However, the structural basis of the mechanism underlying fusion inhibition by Arbidol has remained obscure, thereby hindering its further development as a specific and optimized influenza therapeutic. We determined crystal structures of Arbidol in complex with influenza virus HA from pandemic 1968 H3N2 and recent 2013 H7N9 viruses. Arbidol binds in a hydrophobic cavity in the HA trimer stem at the interface between two protomers. This cavity is distal to the conserved epitope targeted by broadly neutralizing stem antibodies and is ~16 Å from the fusion peptide. Arbidol primarily makes hydrophobic interactions with the binding site but also induces some conformational rearrangements to form a network of inter- and intraprotomer salt bridges. By functioning as molecular glue, Arbidol stabilizes the prefusion conformation of HA that inhibits the large conformational rearrangements associated with membrane fusion in the low pH of the endosome. This unique binding mode compared with the small-molecule inhibitors of other class I fusion proteins enhances our understanding of how small molecules can function as fusion inhibitors and guides the development of broad-spectrum therapeutics against influenza virus.

  14. The antiviral drug acyclovir is a slow-binding inhibitor of (D)-amino acid oxidase.

    Science.gov (United States)

    Katane, Masumi; Matsuda, Satsuki; Saitoh, Yasuaki; Sekine, Masae; Furuchi, Takemitsu; Koyama, Nobuhiro; Nakagome, Izumi; Tomoda, Hiroshi; Hirono, Shuichi; Homma, Hiroshi

    2013-08-20

    d-Amino acid oxidase (DAO) is a degradative enzyme that is stereospecific for d-amino acids, including d-serine and d-alanine, which are believed to be coagonists of the N-methyl-d-aspartate (NMDA) receptor. To identify a new class of DAO inhibitor(s) that can be used to elucidate the molecular details of the active site environment of DAO, manifold biologically active compounds of microbial origin and pre-existing drugs were screened for their ability to inhibit DAO activity, and several compounds were identified as candidates. One of these compounds, acyclovir (ACV), a well-known antiviral drug used for the treatment of herpesvirus infections, was characterized and evaluated as a novel DAO inhibitor in vitro. Analysis showed that ACV acts on DAO as a reversible slow-binding inhibitor, and interestingly, the time required to achieve equilibrium between DAO, ACV, and the DAO/ACV complex was highly dependent on temperature. The binding mechanism of ACV to DAO was investigated in detail by several approaches, including kinetic analysis, structural modeling of DAO complexed with ACV, and site-specific mutagenesis of an active site residue postulated to be involved in the binding of ACV. The results confirm that ACV is a novel, active site-directed inhibitor of DAO that can be a valuable tool for investigating the structure-function relationships of DAO, including the molecular details of the active site environment of DAO. In particular, it appears that ACV can serve as an active site probe to study the structural basis of temperature-induced conformational changes of DAO.

  15. Synthesis, Isolation and Characterization of Process-Related Impurities in Oseltamivir Phosphate

    Directory of Open Access Journals (Sweden)

    Yogesh Kumar Sharma

    2012-01-01

    Full Text Available Three known impurities in oseltamivir phosphate bulk drug at level 0.1% (ranging from 0.05-0.1% were detected by gradient reverse phase high performance liquid chromatography. These impurities were preliminarily identified by the mass number of the impurities. Different experiments were conducted and finally the known impurities were synthesized and characterized.

  16. Oseltamivir-resistant influenza virus A (H1N1), Europe, 2007/08 season.

    NARCIS (Netherlands)

    Meijer, A.; Lackenby, A.; Hungnes, O.; Lina, B.; Werf, S. van der; Schweiger, B.; Opp, M.; Paget, J.; Kassteele, J. van de; Hay, A.; Zambon, M.

    2009-01-01

    In Europe, the 2007/08 winter season was dominated by influenza virus A (H1N1) circulation through week 7, followed by influenza B virus from week 8 onward. Oseltamivir-resistant influenza viruses A (H1N1) (ORVs) with H275Y mutation in the neuraminidase emerged independently of drug use. By country,

  17. Arbidol (Umifenovir): A broad-spectrum antiviral drug that inhibits medically important arthropod-borne flaviviruses

    Czech Academy of Sciences Publication Activity Database

    Haviernik, J.; Štefánik, M.; Fojtíková, M.; Kali, S.; Tordo, N.; Rudolf, Ivo; Hubálek, Zdeněk; Eyer, Luděk; Růžek, Daniel

    2018-01-01

    Roč. 10, č. 4 (2018), č. článku 184. ISSN 1999-4915 R&D Projects: GA ČR(CZ) GA16-20054S Institutional support: RVO:68081766 ; RVO:60077344 Keywords : Antiviral activity * Arbidol * Cell-type dependent antiviral effect * Cytotoxicity * Flavivirus * Umifenovir Subject RIV: EE - Microbiology, Virology OBOR OECD: Virology Impact factor: 3.465, year: 2016

  18. Restrictions for reimbursement of interferon-free direct-acting antiviral drugs for HCV infection in Europe

    DEFF Research Database (Denmark)

    Marshall, Alison D; Cunningham, Evan B; Nielsen, Stine

    2018-01-01

    All-oral direct-acting antiviral drugs (DAAs) for hepatitis C virus, which have response rates of 95% or more, represent a major clinical advance. However, the high list price of DAAs has led many governments to restrict their reimbursement. We reviewed the availability of, and national criteria...... at stage F2 or higher, 29 (83%) had no listed restrictions based on drug or alcohol use, 33 (94%) required a specialist prescriber, and 34 (97%) had no additional restrictions for people co-infected with HIV and hepatitis C virus. These findings have implications for meeting WHO targets, with evidence...

  19. Spectroscopic, thermal and X-ray structural study of the antiparasitic and antiviral drug nitazoxanide

    Science.gov (United States)

    Bruno, Flavia P.; Caira, Mino R.; Monti, Gustavo A.; Kassuha, Diego E.; Sperandeo, Norma R.

    2010-12-01

    Nitazoxanide [2-(acetyloxy)- N-(5-nitro-2-thiazolyl)benzamide, NTZ] is a potent antiparasitic and antiviral agent recently approved. The anti-protozoal activity of NTZ is believed to be due to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme dependent electron transfer reaction. As drug-enzyme interactions are governed by the three-dimensional stereochemistry of both participants, the crystal structure of NTZ was determined for the first time to identify the conformational preferences that may be related to biological activity. NTZ crystallizes as the carboxamide tautomer in the orthorhombic system, space group Pna2 1 with the following parameters at 100(2) K: a = 14.302(2) Å, b = 5.2800(8) Å, c = 33.183(5) Å, V = 2505.8(6) Å 3, Z = 8, D x = 1.629 g cm -3, R = 0.0319, wR2 = 0.0799 for 5121 reflections. In addition, the spectroscopic and thermal properties were determined and related to the molecular structure. The 13C CPMAS NMR spectra showed resolved signals for each carbon of NTZ, some signals being broad due to residual dipolar interaction with quadrupolar 14N nuclei. In particular, the resonance at about 127 ppm showed multiplicity, indicating more than one molecule in the asymmetric unit and this is consistent with the crystallographic data. The DSC and TG data revealed that NTZ shows a single DSC melting peak with extrapolated onset at 201 °C which is accompanied by a TG weight loss, indicating that NTZ melts with decomposition.

  20. Structures of Two Coronavirus Main Proteases: Implications for Substrate Binding and Antiviral Drug Design

    Energy Technology Data Exchange (ETDEWEB)

    Xue, Xiaoyu; Yu, Hongwei; Yang, Haitao; Xue, Fei; Wu, Zhixin; Shen, Wei; Li, Jun; Zhou, Zhe; Ding, Yi; Zhao, Qi; Zhang, Xuejun C.; Liao, Ming; Bartlam, Mark; Rao, Zihe (SCAU); (Tsinghua); (Chinese Aca. Sci.)

    2008-07-21

    Coronaviruses (CoVs) can infect humans and multiple species of animals, causing a wide spectrum of diseases. The coronavirus main protease (M{sup pro}), which plays a pivotal role in viral gene expression and replication through the proteolytic processing of replicase polyproteins, is an attractive target for anti-CoV drug design. In this study, the crystal structures of infectious bronchitis virus (IBV) MP{sup pro} and a severe acute respiratory syndrome CoV (SARS-CoV) M{sup pro} mutant (H41A), in complex with an N-terminal autocleavage substrate, were individually determined to elucidate the structural flexibility and substrate binding of M{sup pro}. A monomeric form of IBV M{sup pro} was identified for the first time in CoV M{sup pro} structures. A comparison of these two structures to other available M{sup pro} structures provides new insights for the design of substrate-based inhibitors targeting CoV M{sup pro}s. Furthermore, a Michael acceptor inhibitor (named N3) was cocrystallized with IBV M{sup pro} and was found to demonstrate in vitro inactivation of IBV M{sup pro} and potent antiviral activity against IBV in chicken embryos. This provides a feasible animal model for designing wide-spectrum inhibitors against CoV-associated diseases. The structure-based optimization of N3 has yielded two more efficacious lead compounds, N27 and H16, with potent inhibition against SARS-CoV M{sup pro}.

  1. Ophthalmic antiviral chemotherapy : An overview

    Directory of Open Access Journals (Sweden)

    Athmanathan Sreedharan

    1997-01-01

    Full Text Available Antiviral drug development has been slow due to many factors. One such factor is the difficulty to block the viral replication in the cell without adversely affecting the host cell metabolic activity. Most of the antiviral compounds are analogs of purines and pyramidines. Currently available antiviral drugs mainly inhibit viral nucleic acid synthesis, hence act only on actively replicating viruses. This article presents an overview of some of the commonly used antiviral agents in clinical ophthalmology.

  2. Synthesis and antiviral activity of PB1 component of the influenza A RNA polymerase peptide fragments.

    Science.gov (United States)

    Matusevich, O V; Egorov, V V; Gluzdikov, I A; Titov, M I; Zarubaev, V V; Shtro, A A; Slita, A V; Dukov, M I; Shurygina, A-P S; Smirnova, T D; Kudryavtsev, I V; Vasin, A V; Kiselev, O I

    2015-01-01

    This study is devoted to the antiviral activity of peptide fragments from the PB1 protein - a component of the influenza A RNA polymerase. The antiviral activity of the peptides synthesized was studied in MDCK cell cultures against the pandemic influenza strain A/California/07/2009 (H1N1) pdm09. We found that peptide fragments 6-13, 6-14, 26-30, 395-400, and 531-540 of the PB1 protein were capable of suppressing viral replication in cell culture. Terminal modifications i.e. N-acetylation and C-amidation increased the antiviral properties of the peptides significantly. Peptide PB1 (6-14) with both termini modified showed maximum antiviral activity, its inhibitory activity manifesting itself during the early stages of viral replication. It was also shown that the fluorescent-labeled analog of this peptide was able to penetrate into the cell. The broad range of virus-inhibiting activity of PB1 (6-14) peptide was confirmed using a panel of influenza A viruses of H1, H3 and H5 subtypes including those resistant to oseltamivir, the leading drug in anti-influenza therapy. Thus, short peptide fragments of the PB1 protein could serve as leads for future development of influenza prevention and/or treatment agents. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Increasing oral absorption of polar neuraminidase inhibitors: a prodrug transporter approach applied to oseltamivir analogue.

    Science.gov (United States)

    Gupta, Deepak; Varghese Gupta, Sheeba; Dahan, Arik; Tsume, Yasuhiro; Hilfinger, John; Lee, Kyung-Dall; Amidon, Gordon L

    2013-02-04

    Poor oral absorption is one of the limiting factors in utilizing the full potential of polar antiviral agents. The neuraminidase target site requires a polar chemical structure for high affinity binding, thus limiting oral efficacy of many high affinity ligands. The aim of this study was to overcome this poor oral absorption barrier, utilizing prodrug to target the apical brush border peptide transporter 1 (PEPT1). Guanidine oseltamivir carboxylate (GOCarb) is a highly active polar antiviral agent with insufficient oral bioavailability (4%) to be an effective therapeutic agent. In this report we utilize a carrier-mediated targeted prodrug approach to improve the oral absorption of GOCarb. Acyloxy(alkyl) ester based amino acid linked prodrugs were synthesized and evaluated as potential substrates of mucosal transporters, e.g., PEPT1. Prodrugs were also evaluated for their chemical and enzymatic stability. PEPT1 transport studies included [(3)H]Gly-Sar uptake inhibition in Caco-2 cells and cellular uptake experiments using HeLa cells overexpressing PEPT1. The intestinal membrane permeabilities of the selected prodrugs and the parent drug were then evaluated for epithelial cell transport across Caco-2 monolayers, and in the in situ rat intestinal jejunal perfusion model. Prodrugs exhibited a pH dependent stability with higher stability at acidic pHs. Significant inhibition of uptake (IC(50) 30-fold increase in affinity compared to GOCarb. The l-valyl prodrug exhibited significant enhancement of uptake in PEPT1/HeLa cells and compared favorably with the well-absorbed valacyclovir. Transepithelial permeability across Caco-2 monolayers showed that these amino acid prodrugs have a 2-5-fold increase in permeability as compared to the parent drug and showed that the l-valyl prodrug (P(app) = 1.7 × 10(-6) cm/s) has the potential to be rapidly transported across the epithelial cell apical membrane. Significantly, only the parent drug (GOCarb) appeared in the basolateral

  4. Identification of transformation products of antiviral drugs formed during biological wastewater treatment and their occurrence in the urban water cycle.

    Science.gov (United States)

    Funke, Jan; Prasse, Carsten; Ternes, Thomas A

    2016-07-01

    The fate of five antiviral drugs (abacavir, emtricitabine, ganciclovir, lamivudine and zidovudine) was investigated in biological wastewater treatment. Investigations of degradation kinetics were accompanied by the elucidation of formed transformation products (TPs) using activated sludge lab experiments and subsequent LC-HRMS analysis. Degradation rate constants ranged between 0.46 L d(-1) gSS(-1) (zidovudine) and 55.8 L d(-1) gSS(-1) (abacavir). Despite these differences of the degradation kinetics, the same main biotransformation reaction was observed for all five compounds: oxidation of the terminal hydroxyl-moiety to the corresponding carboxylic acid (formation of carboxy-TPs). In addition, the oxidation of thioether moieties to sulfoxides was observed for emtricitabine and lamivudine. Antiviral drugs were detected in influents of municipal wastewater treatment plants (WWTPs) with concentrations up to 980 ng L(-1) (emtricitabine), while in WWTP effluents mainly the TPs were found with concentration levels up to 1320 ng L(-1) (carboxy-abacavir). Except of zidovudine none of the original antiviral drugs were detected in German rivers and streams, whereas the concentrations of the TPs ranged from 16 ng L(-1) for carboxy-lamivudine up to 750 ng L(-1) for carboxy-acyclovir. These concentrations indicate an appreciable portion from WWTP effluents present in rivers and streams, as well as the high environmental persistence of the carboxy-TPs. As a result three of the carboxylic TPs were detected in finished drinking water. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Tenofovir treatment augments anti-viral immunity against drug-resistant SIV challenge in chronically infected rhesus macaques

    Directory of Open Access Journals (Sweden)

    Marx Preston

    2006-12-01

    Full Text Available Abstract Background Emergence of drug-resistant strains of human immunodeficiency virus type 1 (HIV-1 is a major obstacle to successful antiretroviral therapy (ART in HIV-infected patients. Whether antiviral immunity can augment ART by suppressing replication of drug-resistant HIV-1 in humans is not well understood, but can be explored in non-human primates infected with simian immunodeficiency virus (SIV. Rhesus macaques infected with live, attenuated SIV develop robust SIV-specific immune responses but remain viremic, often at low levels, for periods of months to years, thus providing a model in which to evaluate the contribution of antiviral immunity to drug efficacy. To investigate the extent to which SIV-specific immune responses augment suppression of drug-resistant SIV, rhesus macaques infected with live, attenuated SIVmac239Δnef were treated with the reverse transcriptase (RT inhibitor tenofovir, and then challenged with pathogenic SIVmac055, which has a five-fold reduced sensitivity to tenofovir. Results Replication of SIVmac055 was detected in untreated macaques infected with SIVmac239Δnef, and in tenofovir-treated, naïve control macaques. The majority of macaques infected with SIVmac055 experienced high levels of plasma viremia, rapid CD4+ T cell loss and clinical disease progression. By comparison, macaques infected with SIVmac239Δnef and treated with tenofovir showed no evidence of replicating SIVmac055 in plasma using allele-specific real-time PCR assays with a limit of sensitivity of 50 SIV RNA copies/ml plasma. These animals remained clinically healthy with stable CD4+ T cell counts during three years of follow-up. Both the tenofovir-treated and untreated macaques infected with SIVmac239Δnef had antibody responses to SIV gp130 and p27 antigens and SIV-specific CD8+ T cell responses prior to SIVmac055 challenge, but only those animals receiving concurrent treatment with tenofovir resisted infection with SIVmac055. Conclusion

  6. Quantitative autoradiographic mapping of focal herpes simplex virus encephalitis using a radiolabeled antiviral drug

    International Nuclear Information System (INIS)

    Price, R.

    1984-01-01

    A method of mapping herpes simplex viral infection comprising administering a radiolabeled antiviral active 5-substituted 1-(2'-deoxy-2'-substituted-D-arabinofuranosyl) pyrimidine nucleoside to the infected subject, and scanning the area in which the infection is to be mapped for the radiolabel

  7. Marine natural seaweed products as potential antiviral drugs against Bovine viral diarrhea virus

    Directory of Open Access Journals (Sweden)

    Ana Maria Viana Pinto

    2012-08-01

    Full Text Available Bovine viral diarrhea virus (BVDV is an etiologic agent that causes important economic losses in the world. It is endemic in cattle herds in most parts of the world. The purpose of this study was to evaluate the in vitro cytotoxic effect and antiviral properties of several marine natural products obtained from seaweeds: the indole alkaloid caulerpin (CAV, 1 and three diterpenes: 6-hydroxydichotoma-3,14-diene-1,17-dial (DA, 2, 10,18-diacetoxy-8-hydroxy-2,6-dolabelladiene (DB1, 3 and 8,10,18-trihydroxy-2,6-dolabelladiene (DB3, 4. The screening to evaluate the cytotoxicity of compounds did not show toxic effects to MDBK cells. The antiviral activity of the compounds was measured by the inhibition of the cytopathic effect on infected cells by plaque assay (PA and EC50 values were calculated for CAV (EC=2,0± 5.8, DA (EC 2,8± 7.7, DB1 (EC 2,0±9.7, and DB3 (EC 2,3±7.4. Acyclovir (EC50 322± 5.9 was used in all experiments as the control standard. Although the results of the antiviral activity suggest that all compounds are promising as antiviral agents against BVDV, the Selectivity Index suggests that DB1 is the safest of the compounds tested.

  8. Marine natural seaweed products as potential antiviral drugs against Bovine viral diarrhea virus

    Directory of Open Access Journals (Sweden)

    Ana Maria Viana Pinto

    2012-05-01

    Full Text Available Bovine viral diarrhea virus (BVDV is an etiologic agent that causes important economic losses in the world. It is endemic in cattle herds in most parts of the world. The purpose of this study was to evaluate the in vitro cytotoxic effect and antiviral properties of several marine natural products obtained from seaweeds: the indole alkaloid caulerpin (CAV, 1 and three diterpenes: 6-hydroxydichotoma-3,14-diene-1,17-dial (DA, 2, 10,18-diacetoxy-8-hydroxy-2,6-dolabelladiene (DB1, 3 and 8,10,18-trihydroxy-2,6-dolabelladiene (DB3, 4. The screening to evaluate the cytotoxicity of compounds did not show toxic effects to MDBK cells. The antiviral activity of the compounds was measured by the inhibition of the cytopathic effect on infected cells by plaque assay (PA and EC50 values were calculated for CAV (EC=2,0± 5.8, DA (EC 2,8± 7.7, DB1 (EC 2,0±9.7, and DB3 (EC 2,3±7.4. Acyclovir (EC50 322± 5.9 was used in all experiments as the control standard. Although the results of the antiviral activity suggest that all compounds are promising as antiviral agents against BVDV, the Selectivity Index suggests that DB1 is the safest of the compounds tested.

  9. The Denver Tube Combined with Antiviral Drugs In the Treatment of HBV-related Cirrhosis with Refractory Ascites: A Report of Three Cases

    Directory of Open Access Journals (Sweden)

    Wang Xiao-jin

    2014-03-01

    Full Text Available Treatment of nucleos(tide antiviral drugs for decompensated HBV-related cirrhosis can significantly improve the prognosis. But those patients with refractory ascites possibly deteriorate due to the complications of ascites before any benefit from anti-viral drugs could be observed. Therefore, it is important to find a way to help the patients with HBV-related cirrhosis and refractory ascites to receive the full benefits from antiviral therapy. Peritoneovenous shunt (PVS using Denver tube enables ascites to continuously bypass into systemic circulation, thereby reducing ascites and albumin input and improving quality of life. We report herein 3 cases of decompensated HBV-related cirrhosis with refractory ascites, PVS using Denver tube was combined with lamivudine for antiviral treatment before and after. Then, ascites was alleviated significantly or disapeared and viral responsed well. All patients achieved a satisfactory long-term survival from 6.7 to 14.7 years. It was suggested that the Denver shunt could be used as an adjuvant method to antiviral drugs for decompensated HBV-related cirrhosis with refractory ascites to help the patients reap the full benefits and maximize efficacy of antiviral treatment.

  10. Modelling Hepatitis B Virus Antiviral Therapy and Drug Resistant Mutant Strains

    Science.gov (United States)

    Bernal, Julie; Dix, Trevor; Allison, Lloyd; Bartholomeusz, Angeline; Yuen, Lilly

    Despite the existence of vaccines, the Hepatitis B virus (HBV) is still a serious global health concern. HBV targets liver cells. It has an unusual replication process involving an RNA pre-genome that the reverse transcriptase domain of the viral polymerase protein translates into viral DNA. The reverse transcription process is error prone and together with the high replication rates of the virus, allows the virus to exist as a heterogeneous population of mutants, known as a quasispecies, that can adapt and become resistant to antiviral therapy. This study presents an individual-based model of HBV inside an artificial liver, and associated blood serum, undergoing antiviral therapy. This model aims to provide insights into the evolution of the HBV quasispecies and the individual contribution of HBV mutations in the outcome of therapy.

  11. Meeting report: 4th ISIRV antiviral group conference: Novel antiviral therapies for influenza and other respiratory viruses.

    Science.gov (United States)

    McKimm-Breschkin, Jennifer L; Fry, Alicia M

    2016-05-01

    The International Society for Influenza and other Respiratory Virus Diseases (isirv) held its 4th Antiviral Group Conference at the University of Texas on 2-4 June, 2015. With emerging resistance to the drugs currently licensed for treatment and prophylaxis of influenza viruses, primarily the neuraminidase inhibitor oseltamivir phosphate (Tamiflu) and the M2 inhibitors amantadine and rimantadine, and the lack of effective interventions against other respiratory viruses, the 3-day programme focused on the discovery and development of inhibitors of several virus targets and key host cell factors involved in virus replication or mediating the inflammatory response. Virus targets included the influenza haemagglutinin, neuraminidase and M2 proteins, and both the respiratory syncytial virus and influenza polymerases and nucleoproteins. Therapies for rhinoviruses and MERS and SARS coronaviruses were also discussed. With the emerging development of monoclonal antibodies as therapeutics, the potential implications of antibody-dependent enhancement of disease were also addressed. Topics covered all aspects from structural and molecular biology to preclinical and clinical studies. The importance of suitable clinical trial endpoints and regulatory issues were also discussed from the perspectives of both industry and government. This meeting summary provides an overview, not only for the conference participants, but also for those interested in the current status of antivirals for respiratory viruses. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Nosocomial outbreak of the pandemic Influenza A (H1N1) 2009 in critical hematologic patients during seasonal influenza 2010-2011: detection of oseltamivir resistant variant viruses.

    Science.gov (United States)

    Pollara, Caterina P; Piccinelli, Giorgio; Rossi, Giuseppe; Cattaneo, Chiara; Perandin, Francesca; Corbellini, Silvia; Tomasi, Dolores De; Bonfanti, Carlo

    2013-03-07

    The pandemic influenza A (H1N1) 2009 (H1N1pdm09) virus infection caused illness and death among people worldwide, particularly in hematologic/oncologic patients because influenza infected individuals can shed virus for prolonged periods, thus increasing the chances for the development of drug-resistant strains such as oseltamivir-resistant (OST-r) variant. The aim of our study was to retrospectively evaluate the clinical importance of OST-r variant in circulating strains of the pandemic H1N1pdm09 virus. By means of RT-PCR and Sanger sequencing we analysed the presence of OST-r variant in 76 H1N1pdm09 laboratory-confirmed cases, hospitalized at the hematologic/oncologic ward at Spedali Civili of Brescia -Italy. Out of 76 hospitalized hematologic/oncologic patients, 23 patients (30.2%) were infected by H1N1pdm09 virus. Further investigation revealed that 3 patients were positive for the OST-r variant carrying the H275Y mutation. All the 23 infected patients were immuno-compromised, and were under treatment or had been treated previously with oseltamivir. Three patients died (13%) after admission to intensive care unit and only one of them developed H275Y mutation. Our retrospective observational study shows that pandemic influenza A (H1N1) 2009 virus can cause significant morbidity and even mortality in hematologic/oncologic patients and confirms the high rate of nosocomial transmission of pandemic H1N1pdm09 virus in these critical subjects. Indeed, the reduction in host defences in these hospitalized patients favoured the prolonged use of antiviral therapy and permitted the development of OST-r strain. Strategies as diagnostic vigilance, early isolation of patients and seasonal influenza A(H1N1) vaccination may prevent transmission of influenza in high risk individuals.

  13. Reducing occurrence and severity of pneumonia due to pandemic H1N1 2009 by early oseltamivir administration: a retrospective study in Mexico.

    Directory of Open Access Journals (Sweden)

    Anjarath Lorena Higuera Iglesias

    Full Text Available BACKGROUND: Anti-viral treatment has been used to treat severe or progressive illness due to pandemic H1N1 2009. A main cause of severe illness in pandemic H1N1 2009 is viral pneumonia; however, it is unclear how effective antiviral treatment is against pneumonia when administered >48 hours after symptom onset. Therefore, we aimed to determine how time from symptom onset to antiviral administration affected the effectiveness of antiviral treatment against pneumonia due to pandemic (H1N1 2009. METHODS/PRINCIPAL FINDINGS: A retrospective medical chart review of 442 patients was conducted in a hospital in Mexico. Subjects had tested positive for pandemic H1N1 2009 virus by real-time reverse-transcriptase-polymerase-chain-reaction and were administered oseltamivir. Median time from symptom onset to oseltamivir administration was 5.0 days (range, 0-43. 442 subjects, 71 (16.1% had severe pneumonia which required mechanical ventilation, 191 (43.2% had mild to moderate pneumonia, and 180 (40% did not have pneumonia. Subjects were divided into four groups based on time to oseltamivir administration: ≤2, 3-7, 8-14, and >14 days. Severity of respiratory features was associated with time to treatment, and multivariate analysis indicated that time to oseltamivir administration was associated with severity of respiratory features. A proportional odds model indicated that 50% probability for occurrence of pneumonia of any severity and that of severe pneumonia in patients who would develop pneumonia reached at approximately 3.4 and 21 days, respectively, after symptom onset. Patients with a shorter time to oseltamivir administration were discharged earlier from the hospital. CONCLUSIONS: Earlier initiation of oseltamivir administration after symptom onset significantly reduced occurrence and severity of pneumonia and shortened hospitalization due to pandemic H1N1 2009. Even when administered >48 hours after symptom onset, oseltamivir showed considerable

  14. The neuroprotective action of naringenin on oseltamivir (Tamiflu treated male rats

    Directory of Open Access Journals (Sweden)

    Hoda G. Hegazy

    2016-10-01

    Full Text Available The aim of this study is to evaluate the protective action of naringenin (a flavonoid on the brain functions of oseltamivir treated rats. 24 rats were divided into 4 groups as follows: control, naringenin treated rats (Nar, 50 mg/kg bwt/day, oseltamivir treated rats (Tam, 0.75 mg/kg bwt twice daily and naringenin + oseltamivir treated rats (Nar + Tam. All the drugs were received via oral gavage for five days. The animals on the 5th day were trained in Y maze. Then, on the 6th day, rats were decapitated and the brain was excised for determination of total antioxidant capacity (TAC, total oxidant capacity (TOC, total nitric oxide (TNO, Ca ATPase, total cytochrome P450 (CYP450 contents and brain fatty acid binding proteins FABP7. The results showed a significant increase in the TOC, TNO and CYP450 in Tam treated rats while a significant decrease was noticed in TAC, Ca ATPase and FABP7 in the same group in comparison with the control. Nar + Tam treated rats exhibited a significant decrease in TOC, TNO and CYP450 and a significant increase in TAC, Ca ATPase and FABP7 in comparison with Tam treated rats. An improvement in Y maze behavior and all the investigated parameters was noticed in Nar + Tam treated rats as compared with the oseltamivir treated rats. The results suggest that Nar has a neurophysiological and behavioral protective effect on oseltamivir side effects on the brain functions.

  15. Development and validation of a chemiluminescent immunodetection assay amenable to high throughput screening of antiviral drugs for Nipah and Hendra virus.

    Science.gov (United States)

    Aljofan, Mohamad; Porotto, Matteo; Moscona, Anne; Mungall, Bruce A

    2008-04-01

    There are currently no antiviral drugs approved for the highly lethal Biosafety Level 4 pathogens Nipah and Hendra virus. A number of researchers are developing surrogate assays amenable to Biosafety Level 2 biocontainment but ultimately, the development of a high throughput screening method for directly quantifying these viruses in a Biosafety Level 4 environment will be critical for final evaluation of antiviral drugs identified in surrogate assays, in addition to reducing the time required for effective antiviral drug development. By adapting an existing immunoplaque assay and using enzyme linked immunodetection in a microtitre plate format, the current experiments describe a simple two step assay protocol involving an overnight virus inoculation of Vero cell monolayers (with or without antiviral drug treatment) at Biosafety Level 4, followed by cell fixation and virus inactivation enabling removal of plates from the Biosafety Level 4 laboratory and a subsequent immunodetection assay using a chemiluminescent horse radish peroxidase substrate to be performed at Biosafety Level 2. The analytical sensitivity (limit of detection) of this assay is 100 tissue culture infectious dose50/ml of either Nipah or Hendra virus. In addition this assay enables linear quantitation of virus over three orders of magnitude and is unaffected by dimethyl sulfoxide concentrations of 1% or less. Intra-assay coefficients of variation are acceptable (less than 20%) when detecting a minimum of 1000 tissue culture infectious dose50/ml of either virus although inter-assay variation is considerably greater. By an assessment of efficacies of the broad spectrum antiviral Ribavirin and an experimental fusion inhibitory peptide, this assay reveals a good correlation with previously published fluorescent immunodetection assays. The current experiments describe for the first time, a high throughput screening method amenable for direct assessment of live henipavirus antiviral drug activity.

  16. Oseltamivir-resistant influenza A(H1N1) viruses detected in Europe during season 2007-8 had epidemiologic and clinical characteristics similar to co-circulating susceptible A(H1N1) viruses.

    NARCIS (Netherlands)

    Ciancio B.C.; Meerhoff, T.J.; Kramarz, P.; Bonmarin, I.; Borgen, K.; Boucher, C.A.; Buchholz, U.; Buda, S.; Dijkstra, F.; Dudman, S.; Duwe, S.; Hauge, S.H.; Hungnes, O.; Meijer, A.; Mossong, J.; Paget, W.J.; Phin, N.; Sande, M. van der; Schweiger, B.; Nicoll, A.

    2009-01-01

    During the 2007-08 influenza season, high levels of oseltamivir resistance were detected among influenza A(H1N1) viruses in a number of European countries. We used surveillance data to describe influenza A(H1N1) cases for whom antiviral resistance testing was performed. We pooled data from national

  17. Patterns in influenza antiviral medication use before and during the 2009 H1N1 pandemic, Vaccine Safety Datalink Project, 2000-2010.

    Science.gov (United States)

    Greene, Sharon K; Shay, David K; Yin, Ruihua; McCarthy, Natalie L; Baxter, Roger; Jackson, Michael L; Jacobsen, Steven J; Nordin, James D; Irving, Stephanie A; Naleway, Allison L; Glanz, Jason M; Lieu, Tracy A

    2012-11-01

    U.S. recommendations for using influenza antiviral medications changed in response to viral resistance (to reduce adamantane use) and during the 2009 H1N1 pandemic (to focus on protecting high-risk patients). Little information is available on clinician adherence to these recommendations. We characterized population-based outpatient antiviral medication usage, including diagnosis and testing practices, before and during the pandemic. Eight medical care organizations in the Vaccine Safety Datalink Project provided data on influenza antiviral medication dispensings from January 2000 through June 2010. Dispensing rates were explored in relation to changes in recommendations and influenza diagnosis and laboratory testing frequencies. Factors associated with oseltamivir dispensings in pandemic versus pre-pandemic periods were identified using multivariable logistic regression. Antiviral use changed coincident with recommendations to avoid adamantanes in 2006, to use alternatives to oseltamivir in 2008, and to use oseltamivir during the pandemic. Of 38,019 oseltamivir dispensings during the pandemic, 31% were to patients not assigned an influenza diagnosis, and 97% were to patients not tested for influenza. Oseltamivir was more likely to be dispensed in pandemic versus pre-pandemic periods to patients change antiviral prescribing based on resistance and to focus on high-risk patients during the pandemic. Medications were commonly dispensed to patients without influenza diagnoses and tests, suggesting that antiviral dispensings may offer useful supplemental data for monitoring influenza incidence. © 2012 Blackwell Publishing Ltd.

  18. Zika antiviral chemotherapy: identification of drugs and promising starting points for drug discovery from an FDA-approved library [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Bruno S. Pascoalino

    2016-10-01

    Full Text Available Background The recent epidemics of Zika virus (ZIKV implicated it as the cause of serious and potentially lethal congenital conditions such microcephaly and other central nervous system defects, as well as the development of the Guillain-Barré syndrome in otherwise healthy patients. Recent findings showed that anti-Dengue antibodies are capable of amplifying ZIKV infection by a mechanism similar to antibody-dependent enhancement, increasing the severity of the disease. This scenario becomes potentially catastrophic when the global burden of Dengue and the advent of the newly approved anti-Dengue vaccines in the near future are taken into account. Thus, antiviral chemotherapy should be pursued as a priority strategy to control the spread of the virus and prevent the complications associated with Zika. Methods Here we describe a fast and reliable cell-based, high-content screening assay for discovery of anti-ZIKV compounds. This methodology has been used to screen the National Institute of Health Clinical Collection compound library, a small collection of FDA-approved drugs. Results and conclusion From 725 FDA-approved compounds triaged, 29 (4% were found to have anti-Zika virus activity, of which 22 had confirmed (76% of confirmation by dose-response curves. Five candidates presented selective activity against ZIKV infection and replication in a human cell line. These hits have abroad spectrum of chemotypes and therapeutic uses, offering valuable opportunities for selection of leads for antiviral drug discovery.

  19. Virus-encoded chemokine receptors--putative novel antiviral drug targets

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M

    2005-01-01

    as such a paramount role in the antiviral immune responses. It is therefore not surprising that viruses have found ways to exploit and subvert the chemokine system by means of molecular mimicry. By ancient acts of molecular piracy and by induction and suppression of endogenous genes, viruses have utilized chemokines...... and their receptors to serve a variety of roles in viral life-cycle. This review focuses on the pharmacology of virus-encoded chemokine receptors, yet also the family of virus-encoded chemokines and chemokine-binding proteins will be touched upon. Key properties of the virus-encoded receptors, compared...... to their closest endogenous homologs, are interactions with a wider range of chemokines, which can act as agonists, antagonists and inverse agonists, and the exploitation of many signal transduction pathways. High constitutive activity is another key property of some--but not all--of these receptors. The chemokine...

  20. Oseltamivir resistance among influenza viruses: surveillance in northern Viet Nam, 2009–2012

    Directory of Open Access Journals (Sweden)

    Nguyen Thi Kim Phuong

    2013-06-01

    Full Text Available Introduction: Antiviral resistance has been reported in seasonal influenza A viruses and avian influenza A(H5N1 viruses in Viet Nam, raising concerns about the efficacy of treatment. Methods: We analysed specimens from two sources during the period 2009–2012: influenza-positive samples from influenza-like illness patients at sentinel clinics in northern Viet Nam and isolates from patients with confirmed A(H5N1 infections. Pyrosequencing was used to detect mutations: H275Y [for A(H1N1 and A(H5N1], E119V [for A(H3N2] and I117V [for A(H5N1]. A neuraminidase inhibition assay was used to determine the Inhibitory Concentration 50 (IC50 values for all influenza A and B isolates. Results: There were 341 influenza A positive samples identified; influenza A(H1N1pdm09 was identified most frequently (n = 215. In 2009, oseltamivir resistance was observed in 100% (19 of 19 of seasonal A(H1N1 isolates and 1.4% (3/215 of A(H1N1pdm09 isolates. This H275Y mutation was not found in influenza subtypes A(H5N1 or A(H3N2 isolates. Discussion: In Viet Nam, seasonal and A(H5N1 influenza vaccines are not currently available; thus, effective treatment is required. The presence of oseltamivir-resistant viruses is therefore a concern. Active surveillance for oseltamivir resistance among influenza viruses circulating in Viet Nam should be continued.

  1. Hepatitis C virus cures after direct acting antiviral-related drug-induced liver injury: Case report.

    Science.gov (United States)

    Hasin, Yaakov; Shteingart, Shimon; Dahari, Harel; Gafanovich, Inna; Floru, Sharon; Braun, Marius; Shlomai, Amir; Verstandig, Anthony; Dery, Ilana; Uprichard, Susan L; Cotler, Scott J; Lurie, Yoav

    2016-07-18

    The United States Food and Drug Administration recently warned that the direct acting antiviral (DAA) combination hepatitis C virus (HCV) treatment of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin (PODr + R) can cause severe liver injury in patients with advanced liver disease. Drug induced liver injury was observed in a small number of patients with decompensated cirrhosis treated with other DAAs, but has not been reported in patients with compensated cirrhosis. We report a case of a 74-year-old woman with chronic HCV and Child-Pugh class A cirrhosis (compensated cirrhosis) treated with PODr + R. The patient presented on day 14 of PODr + R therapy with jaundice and new-onset ascites. Her total bilirubin level increased to 23 mg/dL and international normalized ratio rose to 1.65, while aminotransferase levels remained relatively stable. Hepatitis C treatment was discontinued on day 24 and she gradually recovered. Follow-up testing showed that she achieved a sustained virologic response. In conclusion, hepatic decompensation developed within two weeks of starting treatment with PODr + R in a patient with Child-Pugh class A cirrhosis and was characterized by jaundice and ascites with stable aminotransferase levels. Careful monitoring is warranted in patients with HCV-related cirrhosis treated with PODr + R.

  2. Crystal Structures, Thermal Analysis, and Dissolution Behavior of New Solid Forms of the Antiviral Drug Arbidol with Dicarboxylic Acids

    Directory of Open Access Journals (Sweden)

    Alex N. Manin

    2015-12-01

    Full Text Available Salts of the antiviral drug arbidol (umifenovir (Arb with maleate (Mlc and fumarate (Fum anions have been obtained, and their crystal structures have been described. The crystal structure of arbidol maleate has been redetermined by single crystal X-ray diffraction at 180K. A new arbidol cocrystal in zwitterion form with succinic acid (Suc has also been found and characterized. The arbidol zwitterion was not previously seen in any of the drug crystal forms, and the [Arb + Suc] cocrystal seems to be the first found instance. Analysis of the conformational preferences of the arbidol molecule in the crystal structures has shown that it adopts two types of conformations, namely “open” and “closed” ones. Thermal stability of the arbidol salts and cocrystal have been analyzed by means of differential scanning calorimetry, thermogravimetric, and mass-spectrometry analysis. The dissolution study of the arbidol salts and cocrystal performed in aqueous buffer solutions with pH 1.2 and 6.8 has shown that both the salts and the cocrystal dissolve incongruently to form an arbidol hydrochloride monohydrate at pH 1.2 and an arbidol base at pH 6.8, respectively. The cocrystal reaches the highest solubility level in both pH 1.2 and pH 6.8 solutions.

  3. Antiviral Information Management System (AIMS): a prototype for operational innovation in drug development.

    Science.gov (United States)

    Jadhav, Pravin R; Neal, Lauren; Florian, Jeff; Chen, Ying; Naeger, Lisa; Robertson, Sarah; Soon, Guoxing; Birnkrant, Debra

    2010-09-01

    This article presents a prototype for an operational innovation in knowledge management (KM). These operational innovations are geared toward managing knowledge efficiently and accessing all available information by embracing advances in bioinformatics and allied fields. The specific components of the proposed KM system are (1) a database to archive hepatitis C virus (HCV) treatment data in a structured format and retrieve information in a query-capable manner and (2) an automated analysis tool to inform trial design elements for HCV drug development. The proposed framework is intended to benefit drug development by increasing efficiency of dose selection and improving the consistency of advice from US Food and Drug Administration (FDA). It is also hoped that the framework will encourage collaboration among FDA, industry, and academic scientists to guide the HCV drug development process using model-based quantitative analysis techniques.

  4. Community nurse-led initiation of antiviral therapy for chronic hepatitis C in people who inject drugs does not increase uptake of or adherence to treatment.

    Science.gov (United States)

    Lewis, Heather; Kunkel, Jan; Axten, David; Dalton, Jane; Gardner, Hayley; Tippett, Andrew; Wynne, Stephanie; Wilkinson, Mandie; Foster, Graham R

    2016-11-01

    Chronic hepatitis C is common in people who inject drugs (PWID) and this population serves as a reservoir for infection. Treatment levels are low among this group, ranging from 1 to 19%. We explored whether a nurse-initiated community treatment model increased uptake of and adherence to interferon-based therapies. This was a cluster randomized trial of nurse-initiated versus physician-initiated antiviral therapy with pegylated interferon and ribavirin for hepatitis C virus in community clinics (trial registration: ISRCTN07774040). The proportion of participants initiating treatment during follow-up was 10% with nurse-initiated (6/62) and 9% with physician-initiated (6/76) therapy. Adherence was similar in both groups, with only one patient in each arm not adhering to therapy. There were no serious adverse events, but interferon-related side effects were common. Drug and alcohol use did not change during therapy. Despite easy access to antiviral therapy, uptake of treatment was poor, with no significant difference between the groups. Nurse-led initiation of interferon-based antiviral therapy in PWID did not lead to increased uptake of, response to or adherence with treatment. Further service improvement is unlikely to increase the proportion of PWID undergoing antiviral therapy for hepatitis C virus and early adoption of interferon-free regimens may increase the proportion initiating and completing treatment.

  5. Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

    Energy Technology Data Exchange (ETDEWEB)

    Koizumi, Yoshiki [School of Medicine, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan; Nakajim, Syo [Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan; Department of Applied Biological Sciences, Faculty of Science and Technology, Tokyo University of Sciences, Chiba, J; Ohash, Hirofumi [Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan: Department of Applied Biological Sciences, Faculty of Science and Technology, Tokyo University of Sciences, Chiba, J; Tanaka, Yasuhito [Department of Virology and Liver Unit, Nagoya City University Graduate School of Medicinal Sciences, Nagoya, Japan; Wakita, Takaji [Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan; Perelson, Alan S. [Los Alamos National Laboratory; Iwami, Shingo [Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan: PRESTO, JST, Saitama, Japan: CREST, JST, Saitama, Japan; Watashi, Koichi [Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan: Department of Applied Biological Sciences, Faculty of Science and Technology, Tokyo University of Sciences, Chiba, J

    2016-03-21

    Cell culture study combing a mathematical model and computer simulation quantifies the anti-hepatitis C virus drug efficacy at any concentrations and any combinations in preclinical settings, and can obtain rich basic evidences for selecting optimal treatments prior to costly clinical trials.

  6. The RNA-dependent-RNA polymerase, an emerging antiviral drug target for the Hendra virus.

    Science.gov (United States)

    Velkov, Tony; Carbone, Vincenzo; Akter, Jesmin; Sivanesan, Sivashangarie; Li, Jian; Beddoe, Travis; Marsh, Glenn A

    2014-01-01

    Australia is facing a major national medical challenge with the emergence of the Hendra virus (HeV) as a medically and economically important pathogen of humans and animals. Clinical symptoms of human HeV infection can include fever, hypotension, dizziness, encephalitis, respiratory haemorrhage and edema. The window of opportunity for successful patient treatment remains unknown, but is likely to be very narrow. Currently, very few effective therapeutic options are available for the case management of severe HeV infections or the rapid silencing of local outbreaks. This underscores the need for more activity in the drug discovery arena to develop much needed therapeutics that specifically targets this deadly disease. The structural analysis of HeV is very much in its infancy, which leaves many gaps in our understanding of the biology of HeV and makes structure-guided drug design difficult. Structural studies of the viral RNAdependent- RNA polymerase (RdRp), which is the heart of the viral replication machinery, will set the stage for rational drug design and fill a major gap in our understanding of the HeV replication machinery. This review examines the current knowledge based on the multi-domain architecture of the Hendra RdRp and highlights which essential domain functions represent tangible targets for drug development against this deadly disease.

  7. Role of HIV Subtype Diversity in the Development of Resistance to Antiviral Drugs

    Directory of Open Access Journals (Sweden)

    Bluma G. Brenner

    2010-11-01

    Full Text Available Despite the fact that over 90% of HIV-1 infected people worldwide harbor non‑subtype B variants of HIV-1, knowledge of resistance mutations in non-B HIV-1 and their clinical relevance is limited. Due to historical delays in access to antiretroviral therapy (ART on a worldwide basis, the vast majority of reports on drug resistance deal with subtype B infections in developed countries. However, both enzymatic and virological data support the concept that naturally occurring polymorphisms among different nonB subtypes can affect HIV-1 susceptibility to antiretroviral drugs (ARVs, the magnitude of resistance conferred by major mutations, and the propensity to acquire some resistance mutations. Tools need to be optimized to assure accurate measurements of drug susceptibility of non-B subtypes. Furthermore, there is a need to recognize that each subtype may have a distinct resistance profile and that differences in resistance pathways may also impact on cross-resistance and the selection of second-line regimens. It will be essential to pay attention to newer drug combinations in well designed long-term longitudinal studies involving patients infected by viruses of different subtypes.

  8. Antiviral Polymer Therapeutics

    DEFF Research Database (Denmark)

    Smith, Anton Allen Abbotsford

    2014-01-01

    The field of drug delivery is in essence an exercise in engineered pharmacokinetics. Methods of doing so have been developed through the introduction of a vehicle carrying the drug, either by encapsulation or covalent attachment. The emergence of polymer therapeutics in anticancer therapy has...... garnered a great deal of interest due to the substantial room for improvement inherent to conventional chemotherapeutic agents. Chemotherapeutic agents and antiviral agents have a lot of features in common due to both of them typically targeting endogenous targets, unlike antibacterial compounds, though...... the examples of polymer therapeutics being applied as an antiviral treatment are few and far in-between. This work aims to explore antiviral therapeutics, specifically in context of hepatitis virus C (HCV) and HIV. The current treatment of hepatitis C consists of a combination of drugs, of which ribavirin...

  9. Direct-acting antiviral drugs for chronic hepatitis C and risk of major vascular events: a systematic review.

    Science.gov (United States)

    Tamborini Permunian, Eleonora; Gervaso, Lorenzo; Gerdes, Victor; Moja, Lorenzo; Guasti, Luigina; Squizzato, Alessandro

    2018-04-02

    Direct-acting antiviral drugs (DAAs) were recently approved for treating hepatitis C virus-related chronic hepatitis. As advanced chronic liver disease may predispose patients to thrombotic events, it is still uncertain whether DAAs may influence the actual risk of major arterial and venous thrombotic events. We performed a systematic review to assess the incidence of major vascular events in patients receiving DAAs for HCV chronic hepatitis during phase-III randomized controlled trials (RCTs). Two reviewers identified studies through Pubmed database until October 2015. Reporting and incidence of any vascular events were compared with reporting and incidence of major bleeding, anemia (a prespecified safety outcome) and headache (a common non-prespecified safety outcome). 33 RCTs, encompassing 14,764 patients, were included. Only 13 (39%) and 4 (12%) RCTs provide data on any arterial or venous events, respectively. Occurrence of anemia and headache is reported in all studies. Crude unweighted rate of major arterial events is 0.16% (95% CI 0.10-0.24) of the total included population and 0.47% in those 13 RCTs reporting data. Crude unweighted rate of major venous events is 0.03% of the total included population (95% CI 0.01-0.08) and 0.22% in those four RCTs reporting data. Crude unweighted rate of major bleeding is 0.07% (95% CI 0.03-0.1). Incidence of thrombotic events in HCV patients receiving DAAs may be low, but an incorrect estimation cannot be excluded.

  10. Use of oseltamivir in the treatment of canine parvoviral enteritis.

    Science.gov (United States)

    Savigny, Michelle R; Macintire, Douglass K

    2010-02-01

    To determine if oseltamivir with standard therapy for canine parvoviral enteritis ameliorates disease morbidity, mortality, or both; to document significant adverse effects associated with its use. Prospective, randomized, blinded, placebo-controlled clinical trial. University veterinary teaching hospital. Thirty-five dogs. Standard therapy was administered to all dogs. Treatment dogs also received oseltamivir, while control dogs received an equivalent volume of placebo. Dogs were monitored daily according to a clinical scoring system, physical parameters, and diagnostic evaluations. Dogs in the treatment group gained a significant percentage of weight during hospitalization (mean, +2.6%; SD, 7.1%) versus the control dogs (mean, -4.5%; SD, 6.9%) (P=0.006). Treatment dogs did not have any significant changes in their white blood cell (WBC) count, while control dogs experienced a significant drop in their WBC counts during their initial stay. In addition, it did not appear that oseltamivir use was associated with any major adverse clinical effects. While a clear advantage to the use of oseltamivir was not established, a significant weight loss during hospitalization, as well as a significant decrease in WBC count were documented in the control group. No major adverse effects were identified that could be associated with oseltamivir administration. Based on these results, the true role of oseltamivir in the treatment of parvoviral enteritis remains speculative, although it is believed that further investigation is warranted.

  11. Prevalence of Influenza A(H1N1)pdm09 Virus Resistant to Oseltamivir in Shiraz, Iran, During 2012 - 2013.

    Science.gov (United States)

    Khodadad, Nastaran; Moattari, Afagh; Shamsi Shahr Abadi, Mahmoud; Kadivar, Mohammad Rahim; Sarvari, Jamal; Tavakoli, Forough; Pirbonyeh, Neda; Emami, Amir

    2015-08-01

    Oseltamivir has been used as a drug of choice for the prophylaxis and treatment of human influenza A(H1N1)pdm09 infection across the world. However, the most frequently identified oseltamivir resistant virus, influenza A(H1N1)pdm09, exhibit the H275Y substitution in NA gene. This study aimed to determine the prevalence and phylogenetic relationships of oseltamivir resistance in influenza A(H1N1)pdm09 viruses isolated in Shiraz, Iran. Throat swab samples were collected from 200 patients with influenza-like disease from December 2012 until February 2013. A total of 77 influenza A(H1N1)pdm09 positive strains were identified by real-time polymerase chain reaction (PCR). Oseltamivir resistance was detected using quantal assay and nested-PCR method. The NA gene sequencing was conducted to detect oseltamivir-resistant mutants and establish the phylogeny of the prevalent influenza variants. Our results revealed that A(H1N1)pdm09 viruses present in these samples were susceptible to oseltamivir, and contained 5 site specific mutations (V13G, V106I, V241I, N248D, and N369K) in NA gene. These mutations correlated with increasing expression and enzymatic activity of NA protein in the influenza A(H1N1)pdm09 viruses, which were closely related to a main influenza A(H1N1)pdm09 cluster isolated around the world. A(H1N1)pdm09 viruses, identified in this study in Shiraz, Iran, contained 5 site specific mutations and were susceptible to oseltamivir.

  12. Spectroscopic and molecular docking studies on the interaction of antiviral drug nevirapine with calf thymus DNA.

    Science.gov (United States)

    Moghadam, Neda Hosseinpour; Salehzadeh, Sadegh; Shahabadi, Nahid

    2017-09-02

    The interaction of calf thymus DNA with nevirapine at physiological pH was studied by using absorption, circular dichroism, viscosity, differential pulse voltammetry, fluorescence techniques, salt effect studies and computational methods. The drug binds to ct-DNA in a groove binding mode, as shown by slight variation in the viscosity of ct-DNA. Furthermore, competitive fluorimetric studies with Hoechst 33258 indicate that nevirapine binds to DNA via groove binding. Moreover, the structure of nevirapine was optimized by DFT calculations and was used for the molecular docking calculations. The molecular docking results suggested that nevirapine prefers to bind on the minor groove of ct-DNA.

  13. Nano molar detection of acyclovir, an antiviral drug at nanoclay modified carbon paste electrode

    Directory of Open Access Journals (Sweden)

    Nagaraj P. Shetti

    2017-06-01

    Full Text Available A nano level voltammetric sensing method has been developed for determination of acyclovir (ACV at nano clay modified carbon paste sensor by employing cyclic voltammetry (CV and square wave voltammetry (SWV techniques in pH 5.0. The electro-oxidation current of ACV was enhanced two times greater by the modification of the sensor. The modifier nano clay was characterized by utilizing X-ray diffraction (XRD and scanning electronic microscope (SEM. The influence of parameters like scan rate, pH, accumulation time, amount of the modifier and concentration on the peak current of the drug were studied. The effect of ACV concentration variation was studied using SWV technique and got lowest detection limit compared to the earlier reported techniques. The fabricated sensor was employed for the determination of acyclovir in pharmaceutical and biological samples.

  14. Multifunctional dendritic sialopolymersomes as potential antiviral agents: their lectin binding and drug release properties.

    Science.gov (United States)

    Nazemi, Ali; Haeryfar, S M Mansour; Gillies, Elizabeth R

    2013-05-28

    Polymer vesicles, commonly referred to as polymersomes, are self-organized materials that result from the self-assembly of amphiphilic copolymers in solution. Recently, there has been increasing interest in biomedical applications of polymersomes due to the different functions that can be imparted through encapsulation of molecules within the core or membrane or through the introduction of bioactive molecules to the polymersome surface. We describe here the development and study of poly(ethylene oxide)-polycaprolactone polymersomes designed to interact with influenza viruses at two different stages in the infection process. First, the conjugation of the sialic acid N-acetylneuraminic acid (Neu5Ac) to the polymersome surface was designed to inhibit the binding of viral hemagglutinin to sialic acids on host cells, thus preventing viral entry. Second, the incorporation of the neuraminidase inhibitor zanamivir into the polymersome core was designed to prevent the release of progeny virus from the host cells, thus inhibiting viral replication. With the aim of maximizing multivalent effects at the polymersome surface, polyester dendrons functionalized with Neu5Ac were synthesized and conjugated to polymersomes. Binding of the resulting dendritic sialopolymersomes to Limax flavus agglutinin was studied and compared to the sialodendron and a monovalent Neu5Ac derivative using an enzyme-linked lectin inhibition assay. It was found that while the sialodendron exhibited a 17-fold enhancement (per sialoside) relative to the small molecule, the dendritic sialopolymersomes resulted in an almost 2000-fold enhancement in binding affinity. It was also demonstrated that encapsulation of zanamivir into the dendritic sialopolymersomes could be performed with the same efficiency as for naked polymersomes to provide a drug loading of ~35 wt %. Drug release rates were similar for both systems with sustained release over a period of 4 days. Overall, these results suggest the promise of

  15. Development of specific dengue virus 2'-O- and N7-methyltransferase assays for antiviral drug screening.

    Science.gov (United States)

    Barral, K; Sallamand, C; Petzold, C; Coutard, B; Collet, A; Thillier, Y; Zimmermann, J; Vasseur, J-J; Canard, B; Rohayem, J; Debart, F; Decroly, E

    2013-09-01

    Dengue virus (DENV) protein NS5 carries two mRNA cap methyltransferase (MTase) activities involved in the synthesis of a cap structure, (7Me)GpppA(2'OMe)-RNA, at the 5'-end of the viral mRNA. The methylation of the cap guanine at its N7-position (N7-MTase, (7Me)GpppA-RNA) is essential for viral replication. The development of high throughput methods to identify specific inhibitors of N7-MTase is hampered by technical limitations in the large scale synthesis of long capped RNAs. In this work, we describe an efficient method to generate such capped RNA, GpppA(2'OMe)-RNA₇₄, by ligation of two RNA fragments. Then, we use GpppA(2'OMe)-RNA₇₄ as a substrate to assess DENV N7-MTase activity and to develop a robust and specific activity assay. We applied the same ligation procedure to generate (7Me)GpppA-RNA₇₄ in order to characterize the DENV 2'-O-MTase activity specifically on long capped RNA. We next compared the N7- and 2'-O-MTase inhibition effect of 18 molecules, previously proposed to affect MTase activities. These experiments allow the validation of a rapid and sensitive method easily adaptable for high-throughput inhibitor screening in anti-flaviviral drug development. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. Discovery of potential drugs for human-infecting H7N9 virus containing R294K mutation

    Directory of Open Access Journals (Sweden)

    He JY

    2014-12-01

    Full Text Available Jiao-Yu He,1,* Cheng Li,2,* Guo Wu3 1College of Life Sciences and Key Laboratory for Bio-resources of Ministry of Education, Sichuan University, 2College of Agronomy, Sichuan Agricultural University, 3College of Life Sciences, Sichuan Normal University, Chengdu, People’s Republic of China *These authors contributed equally to this work Background: After the first epidemic wave from February through May 2013, the influenza A (H7N9 virus emerged and has followed a second epidemic wave since June 2013. As of June 27, 2014, the outbreak of H7N9 had caused 450 confirmed cases of human infection, with 165 deaths included. The case-fatality rate of all confirmed cases is about 36%, making the H7N9 virus a significant threat to people’s health. At present, neuraminidase inhibitors are the only licensed antiviral medications available to treat H7N9 infections in humans. Oseltamivir is the most commonly used inhibitor, and it is also a front-line drug for the threatening H7N9. Unfortunately, it has been reported that patients treated with oseltamivir can induce R294K (Arg294Lys substitution in the H7N9 virus, which is a rare mutation and can reduce the antiviral efficacy of inhibitors. Even worse, deaths caused by such mutation after oseltamivir treatment have already been reported, indicating that the need to find substitutive neuraminidase inhibitors for currently available drugs to treat drug-resistant H7N9 is really pressing.Materials and methods: First, the structure of H7N9 containing the R294K substitution was downloaded from the Protein Data Bank, and structural information of approved drugs was downloaded from the ZINC (ZINC Is Not Commercial database. Taking oseltamivir carboxylate as a reference drug, we then filtered these molecules through virtual screening to find out potential inhibitors targeting the mutated H7N9 virus. For further evaluation, we carried out a 14 ns molecular dynamic simulation for each H7N9–drug complex and

  17. Oseltamivir-resistant influenza A(H1N1)pdm09 virus associated with high case fatality, India 2015.

    Science.gov (United States)

    Tandel, Kundan; Sharma, Shashi; Dash, Paban Kumar; Parida, ManMohan

    2018-05-01

    Influenza A viruses has been associated with severe global pandemics of high morbidity and mortality with devastating impact on human health and global economy. India witnessed a major outbreak of influenza A(H1N1)pdm09 in 2015. This study comprises detailed investigation of cases died of influenza A(H1N1)pdm09 virus infection during explosive outbreak of 2015, in central part of India. To find out presence of drug resistant virus among patients who died of influenza A(H1N1)pdm09 virus infection and to find out presence of other mutations contributing to the morbidity and mortality. Twenty-two patients having confirmed influenza A(H1N1)pdm09 infection and subsequently died of this infection along with 20 non fatal cases with influenza A(H1N1)pdm09 infection were included in the study. Samples were investigated through RT-PCR/RFLP analysis, followed by nucleotide cycle sequencing of whole NA gene for detection of H275Y amino acid substitution in NA gene responsible for oseltamivir drug resistance. Out of 22 fatal cases, 6 (27.27%) were found to harbor oseltamivir resistant virus strains, whereas the H275Y mutation was not observed among the 20 non fatal cases. Amino acid substitution analysis of complete NA gene revealed V241I, N369K, N386K substitution in all strains playing synergistic role in oseltamivir drug resistance. High morbidity and mortality associated with influenza A(H1N1)pdm09 viruses can be explained by presence of drug resistant strains circulating in this outbreak. Presence of Oseltamivir resistant influenza A(H1N1)pdm09 viruses is a cause of great concern and warrants continuous screening for the circulation of drug resistant strains. © 2017 Wiley Periodicals, Inc.

  18. [THE USE OF THE MODEL MOUSE ICR--VARIOLA VIRUS FOR EVALUATION OF ANTIVIRAL DRUG EFFICACY].

    Science.gov (United States)

    Titova, K A; Sergeev, Al A; Kabanov, A S; Bulychev, L E; Sergeev, Ar A; Galakhova, D O; Shishkina, L N; Zamedyanskaya, A S; Nesterov, A E; Glotov, A G; Taranov, O S; Omigov, V V; Agafonov, A P; Sergeev, A N

    2016-01-01

    Mice of the ICR outbred population were infected intranasally (i/n) with the variola virus (VARV, strain Ind-3a). Clinical signs of the disease did not appear even at the maximum possible dose of the virus 5.2 lg PFU/head (plaque-forming units per head). In this case, 50% infective dose (ID50) of VARV estimated by the presence or absence of the virus in the lungs three days after infection (p.i.) was equal to 2.7 ± 0.4 lg PFU/head. Taking into account the 10% application of the virus in the lungs during the intranasal infection of the mice, it was adequate to 1.7 lg PFU/lungs. This indicates a high infectivity of the VARV for mice comparable to its infectivity for humans. After the i/n infection of mice with the VARV at a dose 30 ID50/ head the highest concentration of the virus detected in the lungs (4.9 ± 0.0 lg PFU/ml of homogenate) and in nasal cavity tissues (4.8 ± 0.0 lg PFU/ml) were observed. The pathomorphological changes in the respiratory organs of the mice infected with the VARV appeared at 3-5 days p.i., and the VARV reproduction noted in the epithelial cells and macrophages were noticed. When the preparations ST-246 and NIOCH-14 were administered orally at a dose of 60 μg/g of mouse weight up to one day before infection, after 2 hours, 1 and 2 days p.i., the VARV reproduction in the lungs after 3 days p.i. decreased by an order of magnitude. Thus, outbred ICR mice infected with the VARV can be used as a laboratory model of the smallpox when evaluating the therapeutic and prophylactic efficacy of the antismallpox drugs.

  19. Oseltamivir-Resistant Influenza Virus A (H1N1), Europe, 2007–08 Season

    OpenAIRE

    Meijer, Adam; Lackenby, Angie; Hungnes, Olav; Lina, Bruno; van der Werf, Sylvie; Schweiger, Brunhilde; Opp, Matthias; Paget, John; van de Kassteele, Jan; Hay, Alan; Zambon, Maria; Buchholz, Udo; Haas, Walter

    2009-01-01

    In Europe, the 2007-08 winter season was dominated by influenza virus A (H1N1) circulation through week 7, followed by influenza B virus from week 8 onward. Oseltamivir-resistant influenza viruses A (H1N1) (ORVs) with H275Y mutation in the neuraminidase emerged independently of drug use. By country, the proportion of ORVs ranged from 0% to 68%, with the highest proportion in Norway. The average weighted prevalence of ORVs across Europe increased gradually over time, from near 0 in week 40 of ...

  20. Kinetic Study of the Alkaline Degradation of Oseltamivir Phosphate and Valacyclovir Hydrochloride using Validated Stability Indicating HPLC

    OpenAIRE

    Ramzia I. Al-Bagary; Asmaa A. El-Zaher; Fahima A. Morsy; Mai M. Fouad

    2014-01-01

    Aqueous alkaline degradation was performed for oseltamivir phosphate (OP) and valacyclovir hydrochloride (VA). Isocratic stability indicating the use of high-performance liquid chromatography (HPLC) was presented for each drug in the presence of its degradation product. The separations were performed using the Nucleosil ODS column and a mobile phase consisting of phosphate buffer (pH = 7), acetonitrile, and methanol 50:25:25 (v/v/v) for OP. For VA separation, a Nucleosil CN column using phosp...

  1. Smallpox Antiviral Drug

    National Research Council Canada - National Science Library

    Hruby, Dennis E; Bolken, Tove C

    2005-01-01

    ...) as a model system, the goal of our currently funded work is to determine whether the 17L cysteine proteinase or the 17L metalloproteinase encoded by VV is the pox virus core protein proteinase (vCPP...

  2. Oseltamivir efficacy, side effects, and safety in children with influenza

    Directory of Open Access Journals (Sweden)

    Eun Sun Seo

    2010-01-01

    Full Text Available Purpose : Although oseltamivir is widely used for treatment of influenza, few clinical studies of its efficacy and resistance have been performed in Korea. We evaluated the safety, side effects, and efficacy of oseltamivir treatment in Korean pediatric patients. Methods : We analyzed 321 children diagnosed with influenza at Busan St. Mary's Medical Center, Korea, between January 2008 and June 2008 (first study period and November 2008 and January 2009 (second study period. Patients were divided into two groups: those receiving oseltamivir treatment for 5 days and those receiving only symptomatic treatment. We investigated clinical symptoms, side effects, and resistance to oseltamivir. We also identified influenza strains and evaluated resistance to oseltamivir using an influenza virus culture. Results : One hundred eighty-six patients were assigned to the treatment group, and 135 were assigned to the control group. The treatment group showed shorter admission duration (4.4 days compared with controls (5.0 days (P=0.000 and had fewer lower respiratory tract complications compared with controls (P&lt;0.05. No significant statistical difference in the virus antigenic type was observed between the groups. In the first study period, virus culture showed influenza B (41.7% vs. 49.6%, A/H3N2 (7.9% vs. 8.4%, and A/H1N1 (9.4% vs. 6.5%. In the second study period, only A/H1N1 (55.3% vs. 50.0% was isolated, except for one case of A (H3N2 in the treatment group. No differences in short- and long-term side effects, including neuropsychologic side effects, were noted between groups. There was no resistance to oseltamivir before or after treatment in the first study period. Conclusion : Based on our results, we suggest that osetalmivir therapy in pediatric patients is effective.

  3. Antiviral Drug Ribavirin Targets Thyroid Cancer Cells by Inhibiting the eIF4E-β-Catenin Axis.

    Science.gov (United States)

    Shen, Xiawei; Zhu, Yali; Xiao, Zuixuan; Dai, Xuemei; Liu, Dan; Li, Lin; Xiao, Baolai

    2017-08-01

    Although eukaryotic translation initiation factor 4E (eIF4E) is important in cancer development and progression, its role in thyroid cancer is not well understood. Ribavirin, an anti-viral drug, has been identified as an eIF4E inhibitor. Herein, we investigated the effects of ribavirin on thyroid cancer and its molecular mechanisms of action. The effects of ribavirin on thyroid cancer was investigated using in vitro cellular assays and in vivo xenograft mouse model. The mechanism of its action on eIF4E-β-catenin axis was examined using genetic and biochemical approaches. We show that ribavirin inhibited proliferation and induced apoptosis in the thyroid cancer cell lines 8505C and FTC-133. Ribavirin inhibited thyroid cancer growth in a xenograft mouse model. Ribavirin also sensitized thyroid cancer's response to paclitaxel. Mechanistically, ribavirin suppressed eIF4E phosphorylation and overexpression of its wildtype and phosphor-mimetic form (S209D) but not of the non-phosphorylatable form (S209A), which rescued the inhibitory effects of ribavirin in thyroid cancer cells. We further demonstrated that ribavirin suppressed phosphorylation and activities of β-catenin and its subsequent gene transcriptional expression. β-Catenin overexpression rescued the effects of ribavirin in thyroid cancer cells. Importantly, we show that eIF4E regulated β-catenin and that the regulation depended on phosphorylation at S209. The in vivo inhibitory effects of ribavirin on phosphorylation of eIF4E and β-catenin were also observed in thyroid tumor. Our data clearly demonstrate that ribavirin acts on thyroid cancer cells by inhibiting eIF4E/β-catenin signaling. Our findings suggest that ribavirin has the potential to be repurposed for thyroid cancer treatment and also highlight the therapeutic value of inhibiting eIF4E-β-catenin in thyroid cancer. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

  4. Research priorities to achieve universal access to hepatitis C prevention, management and direct-acting antiviral treatment among people who inject drugs

    DEFF Research Database (Denmark)

    Grebely, Jason; Bruneau, Julie; Lazarus, Jeffrey V

    2017-01-01

    of HCV infection among current PWID also remains high in many settings. Morbidity and mortality due to liver disease among PWID with HCV infection continues to increase, despite the advent of well-tolerated, simple interferon-free direct-acting antiviral (DAA) HCV regimens with cure rates >95......, gaps in research, and develop research priorities. Topics for discussion included the epidemiology of injecting drug use, HCV, and HIV among PWID, HCV prevention, HCV testing, linkage to HCV care and treatment, DAA treatment for HCV infection, and reinfection following successful treatment. This paper...

  5. Human γδ T Cell Receptor Repertoires in Peripheral Blood Remain Stable Despite Clearance of Persistent Hepatitis C Virus Infection by Direct-Acting Antiviral Drug Therapy

    Directory of Open Access Journals (Sweden)

    Sarina Ravens

    2018-03-01

    Full Text Available Human γδ T cells can contribute to clearance of hepatitis C virus (HCV infection but also mediate liver inflammation. This study aimed to understand the clonal distribution of γδ T cells in peripheral blood of chronic HCV patients and following HCV clearance by interferon-free direct-acting antiviral drug therapies. To this end, γδ T cell receptor (TCR repertoires were monitored by mRNA-based next-generation sequencing. While the percentage of Vγ9+ T cells was higher in patients with elevated liver enzymes and a few expanded Vδ3 clones could be identified in peripheral blood of 23 HCV-infected non-cirrhotic patients, overall clonality and complexity of γδ TCR repertoires were largely comparable to those of matched healthy donors. Monitoring eight chronic HCV patients before, during and up to 1 year after therapy revealed that direct-acting antiviral (DAA drug therapies induced only minor alterations of TRG and TRD repertoires of Vγ9+ and Vγ9− cells. Together, we show that peripheral γδ TCR repertoires display a high stability (1 by chronic HCV infection in the absence of liver cirrhosis and (2 by HCV clearance in the course of DAA drug therapy.

  6. Oseltamivir use and severe abnormal behavior in Japanese children and adolescents with influenza: Is a self-controlled case series study applicable?

    Science.gov (United States)

    Fukushima, Wakaba; Ozasa, Kotaro; Okumura, Akihisa; Mori, Masaaki; Hosoya, Mitsuaki; Nakano, Takashi; Tanabe, Takuya; Yamaguchi, Naoto; Suzuki, Hiroshi; Mori, Mitsuru; Hatayama, Hideaki; Ochiai, Hirotaka; Kondo, Kyoko; Ito, Kazuya; Ohfuji, Satoko; Nakamura, Yosikazu; Hirota, Yoshio

    2017-08-24

    Since the 1990s, self-controlled designs including self-controlled case series (SCCS) studies have been occasionally used in post-marketing evaluation of drug or vaccine safety. An SCCS study was tentatively applied to evaluate the relationship between oseltamivir use and abnormal behavior Type A (serious abnormal behavior potentially leading to an accident or harm to another person) in influenza patients. From the original prospective cohort study with approximately 10,000 Japanese children and adolescents with influenza (aged collaborating hospitals/clinics were analyzed. We hypothesized four combination patterns of the effect period (i.e., the period that effect of oseltamivir on occurrence of abnormal behavior Type A is likely) and the control period. Mantel-Haenszel rate ratio (M-H RR) and its 95% confidence interval (CI) were calculated as the relative risk estimate. Among 28 subjects in the SCCS study, 24 subjects (86%) were administered oseltamivir and 4 subjects (14%) were not. Abnormal behavior Type A was more likely to occur in the effect period than the control period in every pattern (M-H RR: 1.90-29.1). We observed the highest estimate when the effect period was set between the initial intake of oseltamivir and T max (M-H RR: 29.1, 95% CI: 4.21-201). Abnormal behavior Type A was more likely to develop up to approximately 30 times during the period between the initial intake of oseltamivir and T max . However, this period overlapped with the early period of influenza where high fever was observed. Since useful approaches to control the influence of the natural disease course of influenza were not available in this study, we could not deny the possibility that abnormal behavior was induced by influenza itself. The SCCS study was not an optimal method to evaluate the relationship between oseltamivir use and abnormal behavior. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Influenza virus resistance to oseltamivir: what are the implications?

    NARCIS (Netherlands)

    Fleming, D.M.; Elliot, A.J.; Meijer, A.; Paget, W.J.

    2009-01-01

    Influenza caused by an oseltamivir-resistant influenza A(H1N1) virus was widespread across Europe during the 2007–08 winter. About 25% of A(H1N1) viruses tested in the European Influenza Surveillance Scheme (EISS) were resistant with an H274Y mutation in the neuraminidase glycoprotein. Early

  8. Published sequences do not support transfer of oseltamivir resistance mutations from avian to human influenza A virus strains.

    Science.gov (United States)

    Norberg, Peter; Lindh, Magnus; Olofsson, Sigvard

    2015-03-28

    Tamiflu (oseltamivir phosphate ester, OE) is a widely used antiviral active against influenza A virus. Its active metabolite, oseltamivir carboxylate (OC), is chemically stable and secreted into wastewater treatment plants. OC contamination of natural habitats of waterfowl might induce OC resistance in influenza viruses persistently infecting waterfowl, and lead to transfer of OC-resistance from avian to human influenza. The aim of this study was to evaluate whether such has occurred. A genomics approach including phylogenetic analysis and probability calculations for homologous recombination was applied on altogether 19,755 neuraminidase (N1 and N2) genes from virus sampled in humans and birds, with and without resistance mutations. No evidence for transfer of OE resistance mutations from avian to human N genes was obtained, and events suggesting recombination between human and avian influenza virus variants could not be traced in the sequence material studied. The results indicate that resistance in influenza viruses infecting humans is due to the selection pressure posed by the global OE administration in humans rather than transfer from avian influenza A virus strains carrying mutations induced by environmental exposure to OC.

  9. Bench to Bed Evidences for Pharmacokinetic and Pharmacodynamic Interactions Involving Oseltamivir and Chinese Medicine

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    Qi Chang

    2014-01-01

    Full Text Available Oseltamivir (OA, an ethyl ester prodrug of oseltamivir carboxylate (OC, is clinically used as a potent and selective inhibitor of neuraminidase. Chinese medicines have been advocated to combine with conventional drug for avian influenza. The current study aims to investigate the potential pharmacokinetic and pharmacodynamic interactions of a Chinese medicine formula, namely, Yin Qiao San and Sang Ju Yin (CMF1, commonly used for anti-influenza in combination with OA in both rat and human, and to reveal the underlined mechanisms. It was found that although Cmax, AUC and urinary recovery of OC, as well as metabolic ratio (AUCOC/AUCOA, were significantly decreased in a dose-dependent manner following combination use of CMF1 and OA in rat studies (P<0.01, such coadministration in 14 healthy volunteers only resulted in a trend of minor decrease in the related parameters. Further mechanistic studies found that although CMF1 could reduce absorption and metabolism of OA, it appears to enhance viral inhibition of OA (P<0.01. In summary, although there was potential interaction between OA and CMF1 found in rat studies, its clinical impact was expected to be minimal. The coadministration of OA and CMF1 at the clinical recommended dosages is, therefore, considered to be safe.

  10. Oseltamivir-Resistant Influenza Virus A (H1N1), Europe, 2007–08 Season

    Science.gov (United States)

    Lackenby, Angie; Hungnes, Olav; Lina, Bruno; van der Werf, Sylvie; Schweiger, Brunhilde; Opp, Matthias; Paget, John; van de Kassteele, Jan; Hay, Alan; Zambon, Maria

    2009-01-01

    In Europe, the 2007–08 winter season was dominated by influenza virus A (H1N1) circulation through week 7, followed by influenza B virus from week 8 onward. Oseltamivir-resistant influenza viruses A (H1N1) (ORVs) with H275Y mutation in the neuraminidase emerged independently of drug use. By country, the proportion of ORVs ranged from 0% to 68%, with the highest proportion in Norway. The average weighted prevalence of ORVs across Europe increased gradually over time, from near 0 in week 40 of 2007 to 56% in week 19 of 2008 (mean 20%). Neuraminidase genes of ORVs possessing the H275Y substitution formed a homogeneous subgroup closely related to, but distinguishable from, those of oseltamivir-sensitive influenza viruses A (H1N1). Minor variants of ORVs emerged independently, indicating multiclonal ORVs. Overall, the clinical effect of ORVs in Europe, measured by influenza-like illness or acute respiratory infection, was unremarkable and consistent with normal seasonal activity. PMID:19331731

  11. Efficacy of combined antiviral therapy with pegylated interferon α-2a and ribavirin for chronic hepatitis C infection in intravenous drug users

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    Ružić Maja

    2010-01-01

    Full Text Available Introduction. Hepatitis C Virus infection represents not just a medical, but also a socio-economic problem. It is estimated that among 170 million infected, 60% belongs to the category of intravenous drug users (IDUs. Objective. The aim of this paper was to compare the response to the combined therapy of pegylated interferon alfa 2a and ribavirin, in the group of patients with HCV infection who were intravenous drug users (IDUs and in patients who were identified in the other way of transmission of HCV. Also to identify the influence of the therapy on diseases of addiction, during the course of HCV infection and on the effects of the combined therapy of pegylated interferon alfa 2a and ribavirin. Methods. We conducted a retrospective-prospective study, on 60 patients, treated with combined antiviral therapy-pegylated interferon alfa 2a and ribavirin. 30 patients were from the group of IDUs, and 30 patients from other epidemiological groups. Results. There were significant differences between the age of the patients (30.2±7.1 vs. 39.3±11.2 years; p=0.002, but no significant difference in the duration of the HCV infection between the two groups of patients (8.9±7.4 vs. 13.1±7.0 years; p>0.05. A large number of the patients in the group of IDUs had a problem with the abstinence of the drug abuse. In this group, there was the influence of alcohol (30% and other substances with potential hepatotoxicity: marihuana (23.3% and psycho-active drugs (73.6%. Staging of the liver fibrosis was not influenced by those two parameters and was similar in both groups (p>0.05. The genotype 3a was dominant in intravenous drug users (50.0% and genotype 1b in the control group of the patients (76.6%. In both groups, SVR was achieved at a higher percentage (86% vs. 70.00%; p>0.05, but among the intravenous drug users the relapses of HCV infection were at a lower percentage (3.3% vs. 20.0%; p=0.044. Side effects were noticed in solitary cases in both of the examined

  12. Reassortment and mutations associated with emergence and spread of oseltamivir-resistant seasonal influenza A/H1N1 viruses in 2005-2009.

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    Ji-Rong Yang

    Full Text Available A dramatic increase in the frequency of the H275Y mutation in the neuraminidase (NA, conferring resistance to oseltamivir, has been detected in human seasonal influenza A/H1N1 viruses since the influenza season of 2007-2008. The resistant viruses emerged in the ratio of 14.3% and quickly reached 100% in Taiwan from September to December 2008. To explore the mechanisms responsible for emergence and spread of the resistant viruses, we analyzed the complete genome sequences of 25 viruses collected during 2005-2009 in Taiwan, which were chosen from various clade viruses, 1, 2A, 2B-1, 2B-2, 2C-1 and 2C-2 by the classification of hemagglutinin (HA sequences. Our data revealed that the dominant variant, clade 2B-1, in the 2007-2008 influenza emerged through an intra-subtype 4+4 reassortment between clade 1 and 2 viruses. The dominant variant acquired additional substitutions, including A206T in HA, H275Y and D354G in NA, L30R and H41P in PB1-F2, and V411I and P453S in basic polymerase 2 (PB2 proteins and subsequently caused the 2008-2009 influenza epidemic in Taiwan, accompanying the widespread oseltamivir-resistant viruses. We also characterized another 3+5 reassortant virus which became double resistant to oseltamivir and amantadine. Comparison of oseltamivir-resistant influenza A/H1N1 viruses belonging to various clades in our study highlighted that both reassortment and mutations were associated with emergence and spread of these viruses and the specific mutation, H275Y, conferring to antiviral resistance, was acquired in a hitch-hiking mechanism during the viral evolutionary processes.

  13. Inhibition of CRM1-mediated nuclear export of influenza A nucleoprotein and nuclear export protein as a novel target for antiviral drug development.

    Science.gov (United States)

    Chutiwitoonchai, Nopporn; Mano, Takafumi; Kakisaka, Michinori; Sato, Hirotaka; Kondoh, Yasumitsu; Osada, Hiroyuki; Kotani, Osamu; Yokoyama, Masaru; Sato, Hironori; Aida, Yoko

    2017-07-01

    An anti-influenza compound, DP2392-E10 based on inhibition of the nuclear export function of the viral nucleoprotein-nuclear export signal 3 (NP-NES3) domain was successfully identified by our previous high-throughput screening system. Here, we demonstrated that DP2392-E10 exerts its antiviral effect by inhibiting replication of a broad range of influenza A subtypes. In regard to the molecular mechanism, we revealed that DP2392-E10 inhibits nuclear export of both viral NP and nuclear export protein (NEP). More specifically, in vitro pull-down assays revealed that DP2392-E10 directly binds cellular CRM1, which mediates nuclear export of NP and NEP. In silico docking suggested that DP2392-E10 binds at a region close to the HEAT9 and HEAT10 domains of CRM1. Together, these results indicate that the CRM1-mediated nuclear export function of influenza virus represents a new potential target for antiviral drug development, and also provide a core structure for a novel class of inhibitors that target this function. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Diversity of Pharmacological Properties in Chinese and European Medicinal Plants: Cytotoxicity, Antiviral and Antitrypanosomal Screening of 82 Herbal Drugs

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    Thomas Efferth

    2011-09-01

    Full Text Available In an extensive screening, the antiviral, antitrypanosomal and anticancer properties of extracts from 82 plants used in traditional Chinese medicine and European phytomedicine were determined. Several promising plants that were highly effective against hepatitis B virus (HBV, bovine viral diarrhoea virus (BVDV—a flavivirus used here as a surrogate in vitro model of hepatitis C virus, trypanosomes (Trypanosoma brucei brucei and several cancer cell lines were identified. Six aqueous extracts from Celosia cristata, Ophioglossum vulgatum, Houttuynia cordata, Selaginella tamariscina, Alpinia galanga and Alpinia oxyphylla showed significant antiviral effects against BVDV without toxic effects on host embryonic bovine trachea (EBTr cells, while Evodia lepta, Hedyotis diffusa and Glycyrrhiza spp. demonstrated promising activities against the HBV without toxic effects on host human hepatoblastoma cells transfected with HBV-DNA (HepG2 2.2.15 cells. Seven organic extracts from Alpinia oxyphylla, Coptis chinensis, Kadsura longipedunculata, Arctium lappa, Panax ginseng, Panax notoginseng and Saposhnikovia divaricata inhibited T. b. brucei. Moreover, among fifteen water extracts that combined high antiproliferative activity (IC50 0.5–20 µg/mL and low acute in vitro toxicity (0–10% reduction in cell viability at IC50, Coptis chinensis presented the best beneficial characteristics. In conclusion, traditional herbal medicine from Europe and China still has a potential for new therapeutic targets and therapeutic applications.

  15. Self-interest versus group-interest in antiviral control

    OpenAIRE

    Boven, M. van; Klinkenberg, D.; Pen, I.; Weissing, F.J.; Heesterbeek, J.A.P.

    2008-01-01

    Antiviral agents have been hailed to hold considerable promise for the treatment and prevention of emerging viral diseases like H5N1 avian influenza and SARS. However, antiviral drugs are not completely harmless, and the conditions under which individuals are willing to participate in a large-scale antiviral drug treatment program are as yet unknown. We provide population dynamical and game theoretical analyses of large-scale prophylactic antiviral treatment programs. Throughout we compare th...

  16. OSELTAMIVIR APPLICATION AMONG HIV-INFECTED CHILDREN, SUFFERING FROM THE FLU

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    Yu.A. Fomin

    2007-01-01

    Full Text Available The article provides the Oseltamivir application experience in flu treatment among HIV-infected children. The researchers showed that Oseltamivir is an effective medication for the given category of patients, reducing duration of the catarrhal syndrome and intoxication signs. The undesirable phenomena related to the medication intake proved to be transient and called for no cancellation of its use.Key words: children, hiv infection, flu, Oseltamivir.

  17. Oseltamivir-resistant pandemic (H1N12009 in Yemen - case report

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    Al-Kohlani Abdulhakeem

    2010-05-01

    Full Text Available Abstract Background During the influenza season of 2007-08, oseltamivir-resistant influenza A (H1N1 viruses emerged in several countries in Europe, North America, and Asia. Despite substantial prevalence of oseltamivir-resistant viruses, few data are available on the clinical profile of subjects infected with these viruses. Objectives: to describe the first oseltamivir-resistant (H1N1 influenza virus pandemic 2009 from the Eastern Mediterranean Region including Yemen and to determine the evidence by clinical presentation of children infected with these oseltamivir - resistant viruses. Methodology History, physical examination and laboratory investigations including Complete Blood Count, chest x-ray, blood cultures, CSF examination, LFTs, RFTs, blood for sugar, H1N1 test and oseltamivir resistance test. Results Nasal swabs indicated positivity on both H1N1 test and the RNP gene (Human R Nase P gene that serves as internal positive control for Human RNA. Both clinical specimens presented the mutation S31N in the M2 gene associated with resistance to adamantanes and H274Y in NA gene associated with resistance to oseltamivir. This was the first diagnosed case of resistance to oseltamivir in Yemen and also it is the first reported case of oseltamivir resistance virus in the Eastern Mediterranean Region. Conclusion The pattern of resistance found in the oseltamivir resistant isolate collected from Yemen is the same as has been reported elsewhere in other WHO regions. Clinical description and outcomes are not different from what is described elsewhere.

  18. Meta-analysis of the clinical efficacy of combination therapy with traditional Chinese medicine and nucleoside analogue antiviral drugs for chronic hepatitis B

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    REN Shuang

    2013-04-01

    Full Text Available ObjectiveTo investigate whether the collected randomized controlled trials (RCTs published to date have shown that supplemental application of traditional Chinese medicine (TCM improves the outcome of chronic hepatitis B (CHB patients treated with nucleoside analogue antiviral drugs. MethodsLiterature collections on the Chinese Biomedical Literature Database, the Chinese Academic Journal Full-text Database, the Chinese Scientific Journals Database, PubMed, and Embase were searched from inception to July 2012 to identify publications of RCTs comparing the therapeutic efficacy of TCM combined with nucleoside analogues lamivudine (LDM, adefovir (ADV, entecavir (ETV to treat CHB. Inclusion criteria included: patients with CHB for more than six months, serum HbsAg-positivity, 2× upper normal limit (ULN≤alanine aminotransferase (ALT≤10× ULN, hepatitis B virus (HBV DNA-positivity, and no previous antiviral therapy for six months prior to study; a control group receiving a single nucleoside analogue; study treatment time of at least three months. The methodological quality of included RCTs was assessed using the Jadad scale. The meta-analysis was carried out with RevMan 5.0 software. Heterogeneity was examined by Chi-squared test. Pooled data was analyzed by the fixed effects model or random effects model, according to presence of heterogeneity. Publication bias was assessed by funnel plot asymmetry. ResultsA total of 14 RCTs were included in the analysis and comprised 1386 CHB patients with 703 in the trial groups and 683 in the control groups. Only one study had moderate-high methodological quality (Jadad score: 3, and the remaining studies had low methodological quality (Jadad score: 2, n=1; 1, n=12. The outcome measures included: ALT normalization rate, aspartate aminotransferase (AST normalization rate, hepatitis B e antigen (HbeAg-negativity rate, HBeAg seroconversion rate, HBV DNA-negativity rate, and incidence of the LAM-resistance YMDD

  19. Acid-base characterization, coordination properties towards copper(II) ions and DNA interaction studies of ribavirin, an antiviral drug.

    Science.gov (United States)

    Nagaj, Justyna; Starosta, Radosław; Jeżowska-Bojczuk, Małgorzata

    2015-01-01

    We have studied processes of copper(II) ion binding by ribavirin, an antiviral agent used in treating hepatitis C, which is accompanied usually by an increased copper level in the serum and liver tissue. Protonation equilibria and Cu(II) binding were investigated using the UV-visible, EPR and NMR spectroscopic techniques as well as the DFT (density functional theory) calculations. The spectroscopic data suggest that the first complex is formed in the water solution at pH as low as 0.5. In this compound Cu(II) ion is bound to one of the nitrogen atoms from the triazole ring. Above pH6.0, the metal ion is surrounded by two nitrogen and two oxygen atoms from two ligand molecules. The DFT calculations allowed to determine the exact structure of this complex. We found that in the lowest energy isomer two molecules of the ligand coordinate via O and N4 atoms in trans positions. The hypothetical oxidative properties of the investigated system were also examined. It proved not to generate plasmid DNA scission products. However, the calf thymus (CT)-DNA binding studies showed that it reacts with ribavirin and its cupric complex. Moreover, the interaction with the complex is much more efficient. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Emergence of Oseltamivir-Resistant Pandemic (H1N1) 2009 Virus within 48 Hours

    OpenAIRE

    Inoue, Masafumi; Barkham, Timothy; Leo, Yee-Sin; Chan, Kwai-Peng; Chow, Angela; Wong, Christopher W.; Lee, Raphael Tze-Chuen; Maurer-Stroh, Sebastian; Lin, Raymond; Lin, Cui

    2010-01-01

    An oseltamivir-resistant influenza A pandemic (H1N1) 2009 virus evolved and emerged from zero to 52% of detectable virus within 48 hours of a patient’s exposure to oseltamivir. Phylogenetic analysis and data gathered by pyrosequencing and cloning directly on clinical samples suggest that the mutant emerged de novo.

  1. Evolution of multi-drug resistant HCV clones from pre-existing resistant-associated variants during direct-acting antiviral therapy determined by third-generation sequencing

    Science.gov (United States)

    Takeda, Haruhiko; Ueda, Yoshihide; Inuzuka, Tadashi; Yamashita, Yukitaka; Osaki, Yukio; Nasu, Akihiro; Umeda, Makoto; Takemura, Ryo; Seno, Hiroshi; Sekine, Akihiro; Marusawa, Hiroyuki

    2017-03-01

    Resistance-associated variant (RAV) is one of the most significant clinical challenges in treating HCV-infected patients with direct-acting antivirals (DAAs). We investigated the viral dynamics in patients receiving DAAs using third-generation sequencing technology. Among 283 patients with genotype-1b HCV receiving daclatasvir + asunaprevir (DCV/ASV), 32 (11.3%) failed to achieve sustained virological response (SVR). Conventional ultra-deep sequencing of HCV genome was performed in 104 patients (32 non-SVR, 72 SVR), and detected representative RAVs in all non-SVR patients at baseline, including Y93H in 28 (87.5%). Long contiguous sequences spanning NS3 to NS5A regions of each viral clone in 12 sera from 6 representative non-SVR patients were determined by third-generation sequencing, and showed the concurrent presence of several synonymous mutations linked to resistance-associated substitutions in a subpopulation of pre-existing RAVs and dominant isolates at treatment failure. Phylogenetic analyses revealed close genetic distances between pre-existing RAVs and dominant RAVs at treatment failure. In addition, multiple drug-resistant mutations developed on pre-existing RAVs after DCV/ASV in all non-SVR cases. In conclusion, multi-drug resistant viral clones at treatment failure certainly originated from a subpopulation of pre-existing RAVs in HCV-infected patients. Those RAVs were selected for and became dominant with the acquisition of multiple resistance-associated substitutions under DAA treatment pressure.

  2. HCV Drug Resistance Challenges in Japan: The Role of Pre-Existing Variants and Emerging Resistant Strains in Direct Acting Antiviral Therapy

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    Kazuaki Chayama

    2015-10-01

    Full Text Available Sustained virological response (SVR rates have increased dramatically following the approval of direct acting antiviral (DAA therapies. While individual DAAs have a low barrier to resistance, most patients can be successfully treated using DAA combination therapy. However, DAAs are vulnerable to drug resistance, and resistance-associated variants (RAVs may occur naturally prior to DAA therapy or may emerge following drug exposure. While most RAVs are quickly lost in the absence of DAAs, compensatory mutations may reinforce fitness. However, the presence of RAVs does not necessarily preclude successful treatment. Although developments in hepatitis C virus (HCV therapy in Asia have largely paralleled those in the United States, Japan’s July 2014 approval of asunaprevir plus daclatasvir combination therapy as the first all-oral interferon-free therapy was not repeated in the United States. Instead, two different combination therapies were approved: sofosbuvir/ledipasvir and paritaprevir/ritonavir/ombitasvir/dasabuvir. This divergence in treatment approaches may lead to differences in resistance challenges faced by Japan and the US. However, the recent approval of sofosbuvir plus ledipasvir in Japan and the recent submissions of petitions for approval of paritaprevir/ritonavir plus ombitasvir suggest a trend towards a new consensus on emerging DAA regimens.

  3. Study on antiviral activities, drug-likeness and molecular docking of bioactive compounds of Punica granatum L. to Herpes simplex virus - 2 (HSV-2).

    Science.gov (United States)

    Arunkumar, Jagadeesan; Rajarajan, Swaminathan

    2018-03-28

    Herpes simplex virus - 2 (HSV-2) causes lifelong persisting infection in the immunocompromised host and intermittent in healthy individuals with high morbidity in neonatals and also increase the transmission of HIV. Acyclovir is widely used drug to treat HSV-2 infection but it unable to control viral latency and recurrent infection and prolonged usage lead to drug resistance. Plant-based bioactive compounds are the lead structural bio-molecules play an inevitable role as a potential antiviral agent with reduced toxicity. Therefore, there is an urgent need to develop anti-HSV-2 bioactive molecules to prevent viral resistance and control of latent infection. Punica granatum fruit is rich in major bioactive compounds with potential antimicrobial properties. Hence, we evaluated the anti-HSV-2 efficacy of lyophilized extracts and bioactive compounds isolated from fruit peel of P. granatum. As a result, ethanolic peel extract showed significant inhibition at 62.5 μg/ml. Hence, the fruit peel ethanolic extract was subjected for the isolation of bioactive compounds isolation by bioactivity-guided fractionation. Among isolated bioactive compounds, punicalagin showed 100% anti-HSV-2 activity at 31.25 μg/ml with supportive evidence of desirable in silico ADMET properties and strong interactions to selected protein targets of HSV-2 by docking analysis. Copyright © 2018 Elsevier Ltd. All rights reserved.

  4. Contact transmission of influenza virus between ferrets imposes a looser bottleneck than respiratory droplet transmission allowing propagation of antiviral resistance

    Science.gov (United States)

    Frise, Rebecca; Bradley, Konrad; van Doremalen, Neeltje; Galiano, Monica; Elderfield, Ruth A.; Stilwell, Peter; Ashcroft, Jonathan W.; Fernandez-Alonso, Mirian; Miah, Shahjahan; Lackenby, Angie; Roberts, Kim L.; Donnelly, Christl A.; Barclay, Wendy S.

    2016-01-01

    Influenza viruses cause annual seasonal epidemics and occasional pandemics. It is important to elucidate the stringency of bottlenecks during transmission to shed light on mechanisms that underlie the evolution and propagation of antigenic drift, host range switching or drug resistance. The virus spreads between people by different routes, including through the air in droplets and aerosols, and by direct contact. By housing ferrets under different conditions, it is possible to mimic various routes of transmission. Here, we inoculated donor animals with a mixture of two viruses whose genomes differed by one or two reverse engineered synonymous mutations, and measured the transmission of the mixture to exposed sentinel animals. Transmission through the air imposed a tight bottleneck since most recipient animals became infected by only one virus. In contrast, a direct contact transmission chain propagated a mixture of viruses suggesting the dose transferred by this route was higher. From animals with a mixed infection of viruses that were resistant and sensitive to the antiviral drug oseltamivir, resistance was propagated through contact transmission but not by air. These data imply that transmission events with a looser bottleneck can propagate minority variants and may be an important route for influenza evolution. PMID:27430528

  5. The qualitative determination of oseltamivir phosphate in Tamiflu® capsule by cyclic voltammetry

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    Avramov-Ivić Milka L.

    2011-01-01

    Full Text Available A gold electrode was applied in the voltammetric determination of oseltamivir phosphate standard in 0.05 M NaHCO3. Oseltamivir phosphate as a standard and as a component of Tamiflu® capsule exhibited the identical cyclic voltammogram. The peaks originated from excipients in capsule do not appear under the applied electrochemical conditions. The electrochemical method for the qualitative determination of oseltamivir phosphate in Tamiflu® capsule by cyclic voltammetry was developed. The presence of oseltamivir phosphate as standard and as a content of Tamiflu® capsule in electrolyte as well as their concentrations were simultaneously checked by HPLC. The lack of the current/concentration dependency was established. The not pretreated glassy carbon electrode cannot be used for the determination of oseltamivir phosphate under identical experimental conditions presented for gold electrode.

  6. P1-Substituted Symmetry-Based Human Immunodeficiency Virus Protease Inhibitors with Potent Antiviral Activity against Drug-Resistant Viruses

    Energy Technology Data Exchange (ETDEWEB)

    DeGoey, David A.; Grampovnik, David J.; Chen, Hui-Ju; Flosi, William J.; Klein, Larry L.; Dekhtyar, Tatyana; Stoll, Vincent; Mamo, Mulugeta; Molla, Akhteruzzaman; Kempf, Dale J. (Abbott)

    2013-03-07

    Because there is currently no cure for HIV infection, patients must remain on long-term drug therapy, leading to concerns over potential drug side effects and the emergence of drug resistance. For this reason, new and safe antiretroviral agents with improved potency against drug-resistant strains of HIV are needed. A series of HIV protease inhibitors (PIs) with potent activity against both wild-type (WT) virus and drug-resistant strains of HIV was designed and synthesized. The incorporation of substituents with hydrogen bond donor and acceptor groups at the P1 position of our symmetry-based inhibitor series resulted in significant potency improvements against the resistant mutants. By this approach, several compounds, such as 13, 24, and 29, were identified that demonstrated similar or improved potencies compared to 1 against highly mutated strains of HIV derived from patients who previously failed HIV PI therapy. Overall, compound 13 demonstrated the best balance of potency against drug resistant strains of HIV and oral bioavailability in pharmacokinetic studies. X-ray analysis of an HIV PI with an improved resistance profile bound to WT HIV protease is also reported.

  7. The role of lipid-based drug delivery systems for enhancing solubility of highly selective antiviral agent acyclovir.

    Science.gov (United States)

    Kazi, Mohsin; Al-Amri, Khalid A; Alanazi, Fars K

    2017-05-01

    The study aimed to improve the aqueous solubility and dissolution rate of acyclovir (ACV) using self-emulsifying lipid formulations (SEDDS/SMEDDS). ACV was formulated in various SEDDS/SMEDDS using wide ranges of oils (mono-/di-/triglycerides), nonionic surfactants and water-soluble cosolvents with the aid of phase behavior studies. The drug solubility was determined in anhydrous, 10% and 99% diluted formulations. Drug precipitation and release profiles of the SEDDS/SMEDDS were also investigated. The ACV was highly soluble in the formulations containing high concentration of hydrophilic materials. The addition of propylene glycol (PG) significantly enhanced the drug solubility. In addition, with only 1% 0.1 M HCl, the drug solubility improved 10-fold higher without any precipitation. In the dissolution studies, the representative SEDDS/SMEDDS showed superior release profiles (>90% ACV released) than marketed Zovirax® suspension (soluble cosolvent (e.g. PG), were the most suitable systems for ACV due to the extensive drug solubilization and release profile.

  8. Low dose influenza virus challenge in the ferret leads to increased virus shedding and greater sensitivity to oseltamivir.

    Science.gov (United States)

    Marriott, Anthony C; Dove, Brian K; Whittaker, Catherine J; Bruce, Christine; Ryan, Kathryn A; Bean, Thomas J; Rayner, Emma; Pearson, Geoff; Taylor, Irene; Dowall, Stuart; Plank, Jenna; Newman, Edmund; Barclay, Wendy S; Dimmock, Nigel J; Easton, Andrew J; Hallis, Bassam; Silman, Nigel J; Carroll, Miles W

    2014-01-01

    Ferrets are widely used to study human influenza virus infection. Their airway physiology and cell receptor distribution makes them ideal for the analysis of pathogenesis and virus transmission, and for testing the efficacy of anti-influenza interventions and vaccines. The 2009 pandemic influenza virus (H1N1pdm09) induces mild to moderate respiratory disease in infected ferrets, following inoculation with 106 plaque-forming units (pfu) of virus. We have demonstrated that reducing the challenge dose to 102 pfu delays the onset of clinical signs by 1 day, and results in a modest reduction in clinical signs, and a less rapid nasal cavity innate immune response. There was also a delay in virus production in the upper respiratory tract, this was up to 9-fold greater and virus shedding was prolonged. Progression of infection to the lower respiratory tract was not noticeably delayed by the reduction in virus challenge. A dose of 104 pfu gave an infection that was intermediate between those of the 106 pfu and 102 pfu doses. To address the hypothesis that using a more authentic low challenge dose would facilitate a more sensitive model for antiviral efficacy, we used the well-known neuraminidase inhibitor, oseltamivir. Oseltamivir-treated and untreated ferrets were challenged with high (106 pfu) and low (102 pfu) doses of influenza H1N1pdm09 virus. The low dose treated ferrets showed significant delays in innate immune response and virus shedding, delayed onset of pathological changes in the nasal cavity, and reduced pathological changes and viral RNA load in the lung, relative to untreated ferrets. Importantly, these observations were not seen in treated animals when the high dose challenge was used. In summary, low dose challenge gives a disease that more closely parallels the disease parameters of human influenza infection, and provides an improved pre-clinical model for the assessment of influenza therapeutics, and potentially, influenza vaccines.

  9. Antiviral Natural Products and Herbal Medicines

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    Liang-Tzung Lin

    2014-01-01

    Full Text Available Viral infections play an important role in human diseases, and recent outbreaks in the advent of globalization and ease of travel have underscored their prevention as a critical issue in safeguarding public health. Despite the progress made in immunization and drug development, many viruses lack preventive vaccines and efficient antiviral therapies, which are often beset by the generation of viral escape mutants. Thus, identifying novel antiviral drugs is of critical importance and natural products are an excellent source for such discoveries. In this mini-review, we summarize the antiviral effects reported for several natural products and herbal medicines.

  10. Delivering direct acting antiviral therapy for hepatitis C to highly marginalised and current drug injecting populations in a targeted primary health care setting.

    Science.gov (United States)

    Read, Phillip; Lothian, Rebecca; Chronister, Karen; Gilliver, Rosie; Kearley, John; Dore, Gregory J; van Beek, Ingrid

    2017-09-01

    The Kirketon Road Centre (KRC) is a community-based public health facility in Sydney, Australia, that provides healthcare to people who inject drugs (PWID), including hepatitis C virus (HCV) treatment. From March 2016, the Australian Government has provided access to direct-acting antivirals (DAA) for adults with chronic HCV, without liver disease stage or drug and alcohol use restrictions. The aim of this study was to report DAA treatment outcomes among highly marginalised PWID treated at KRC. All individuals initiating DAA treatment at KRC and due for sustained virological response (SVR12) testing by end 2016 were included. Demographic, drug use behaviour, clinical parameters, adherence support and HCV treatment outcomes, including SVR12 were recorded. Factors associated with SVR12, loss-to-follow-up (LTFU) and delayed SVR12 testing (>SVR16) were assessed by multivariate analysis. SVR12 was assessed by intention-to-treat (ITT) and modified ITT, the latter excluding individuals with an end-of-treatment response (ETR) but no SVR12 assessment, or who postponed their SVR12 date due to treatment interruption. A total of 72 individuals commencing DAAs were included, of whom 67% were male, 30% homeless, and 32% Aboriginal. All had a lifetime history of injecting drug use, with 75% having injected within the last six months, and 44% injecting at least weekly; 25% were also enrolled in opioid substitution therapy. Twenty-five (35%) individuals elected to receive an enhanced adherence-support package. Fifty-nine of 72 (82%) individuals due for SVR12 attended for testing, of whom 59/59 (100%) achieved SVR, providing an ITT SVR of 82%. A further six individuals had undetectable HCV RNA at ETR, but no SVR12 assessment, and one interrupted treatment, providing a mITT SVR of 91%. Homelessness was associated with delayed SVR12 testing (OR 24.9 95%CI 2.9-212.8, p=0.003). There was no association between LTFU and frequency of drug injection, last drug injected, or planned

  11. Anti-viral drug treatment along with immune activator IL-2: a control-based mathematical approach for HIV infection

    Science.gov (United States)

    Nath Chatterjee, Amar; Roy, Priti Kumar

    2012-02-01

    Recent development in antiretroviral treatment against HIV can help AIDS patients to fight against HIV. But the question that whether the disease is to be partially or totally eradicated from HIV infected individuals still remains unsolved. Usually, the most effective treatment for the disease is HAART which can only control the disease progression. But as the immune system becomes weak, the patients can not fight against other diseases. Immune cells are activated and proliferated by IL-2 after the identification of antigen. IL-2 production is impaired in HIV positive patients and intermitted administration of immune activator IL-2 together with HAART which is a more effective treatment to fight against the disease. Thus, its expediency is essential and is yet to be explored. In this article we anticipated a mathematical model of the effect of IL-2 together with RTIs therapy in HIV positive patients. Our analytical as well as numerical study shows that the optimal schedule of treatment for best result is to be obtained by systematic drug therapy. But at the last stage of treatment, the infection level raises again due to minimisation of drug dosage. Thus we study the perfect adherence of the drugs and found out if RTIs are taken with sufficient interval then for fixed interval of IL-2 therapy, certain amount of drug dosages may be able to sustain the immune system at pre-infection stage and the infected CD4+T cells are going towards extinction.

  12. Neuraminidase inhibitor R-125489 - A promising drug for treating influenza virus: Steered molecular dynamics approach

    International Nuclear Information System (INIS)

    Mai, Binh Khanh; Li, Mai Suan

    2011-01-01

    Highlights: → We study binding affinity of R-125489 and its prodrug CS-8958 to neuraminidase of pathogenic influenza viruses by molecular dynamics simulations. → It is shown that, in agreement with experiments, R-125489 binds to neuraminidase more tightly than CS-8958. → We predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus. → The high correlation between theoretical and experimental data implies that SMD is a very promising tool for drug design. -- Abstract: Two neuraminidase inhibitors, oseltamivir and zanamivir, are important drug treatments for influenza. Oseltamivir-resistant mutants of the influenza virus A/H1N1 and A/H5N1 have emerged, necessitating the development of new long-acting antiviral agents. One such agent is a new neuraminidase inhibitor R-125489 and its prodrug CS-8958. An atomic level understanding of the nature of this antiviral agents binding is still missing. We address this gap in our knowledge by applying steered molecular dynamics (SMD) simulations to different subtypes of seasonal and highly pathogenic influenza viruses. We show that, in agreement with experiments, R-125489 binds to neuraminidase more tightly than CS-8958. Based on results obtained by SMD and the molecular mechanics-Poisson-Boltzmann surface area method, we predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus as its binding affinity does not vary much across these systems. The high correlation level between theoretically determined rupture forces and experimental data on binding energies for the large number of systems studied here implies that SMD is a promising tool for drug design.

  13. DNA interaction studies of a copper (II) complex containing an antiviral drug, valacyclovir: the effect of metal center on the mode of binding.

    Science.gov (United States)

    Shahabadi, Nahid; Fatahi, Parvin

    2012-07-01

    The water-soluble complex, [Cu(Val)(2)(NO(3))(2)]; in which Val = valacyclovir, an antiviral drug, has been synthesized and characterized by elemental analysis, furier transfer-infrared, hydrogen nuclear magnetic resonance (H NMR), and UV-Vis techniques. The binding of this Cu (II) complex to calf thymus DNA was investigated using fluorimetry, spectrophotometry, circular dichroism, and viscosimetry. In fluorimetric studies, the enthalpy and entropy of the reaction between the complex and calf-thymus DNA (CT-DNA) showed that the reaction is endothermic (ΔH = 208.22 kJ mol(-1); ΔS = 851.35 J mol(-1)K(-1)). The complex showed the absorption hyperchromism in its ultra violet-visible (UV-Vis) spectrum with DNA. The calculated binding constant, K(b), obtained from UV-Vis absorption studies was 2 × 10(5) M(-1). Moreover, the complex induced detectable changes in the circular dichroism spectrum of CT-DNA, as well as changes in its viscosity. The results suggest that this copper (II) complex interacts with CT-DNA via a groove-binding mode.

  14. Study on the interaction of the antiviral drug, zidovudine with DNA using neutral red (NR) and methylene blue (MB) dyes

    Energy Technology Data Exchange (ETDEWEB)

    Shahabadi, Nahid, E-mail: nahidshahabadi@yahoo.com [Department of Inorganic Chemistry, Faculty of Chemistry, Razi University, Kermanshah (Iran, Islamic Republic of); Moghadam, Neda Hossein pour [Department of Inorganic Chemistry, Faculty of Chemistry, Razi University, Kermanshah (Iran, Islamic Republic of)

    2013-02-15

    The interaction between the drug, zidovudine and calf thymus DNA (CT-DNA) in physiological buffer (pH 7.4) was investigated using neutral red (NR) and methylene blue (MB) dyes as a spectral probes by UV-vis absorption and fluorescence spectroscopy, as well as circular dichroism (CD) spectroscopy. The experimental results showed that the conformational changes in DNA helix induced by zidovudine are the reason for the fluorescence quenching of the DNA-NR system. In addition, by increasing zidovudine to DNA-MB solution, the fluorescence has no change. From the experimental results, it was found that zidovudine can cause structural changes on CT-DNA and bind with DNA via groove binding mode. At the same time, the paper proved that conformational changes of DNA can also lead to the fluorescence decrease of DNA-probe systems. - Highlights: Black-Right-Pointing-Pointer Search for new molecular structures which exhibit effective antitumor activities among popular drugs. Black-Right-Pointing-Pointer The DRUG can bind to DNA via groove binding mode. Black-Right-Pointing-Pointer Several spectroscopic techniques have been used in this research.

  15. The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

    Science.gov (United States)

    Stevaert, Annelies

    2016-01-01

    Abstract Influenza viruses cause seasonal epidemics and pandemic outbreaks associated with significant morbidity and mortality, and a huge cost. Since resistance to the existing anti‐influenza drugs is rising, innovative inhibitors with a different mode of action are urgently needed. The influenza polymerase complex is widely recognized as a key drug target, given its critical role in virus replication and high degree of conservation among influenza A (of human or zoonotic origin) and B viruses. We here review the major progress that has been made in recent years in unravelling the structure and functions of this protein complex, enabling structure‐aided drug design toward the core regions of the PA endonuclease, PB1 polymerase, or cap‐binding PB2 subunit. Alternatively, inhibitors may target a protein–protein interaction site, a cellular factor involved in viral RNA synthesis, the viral RNA itself, or the nucleoprotein component of the viral ribonucleoprotein. The latest advances made for these diverse pharmacological targets have yielded agents in advanced (i.e., favipiravir and VX‐787) or early clinical testing, besides several experimental inhibitors in various stages of development, which are all covered here. PMID:27569399

  16. Chiral analysis of anti-acquired immunodeficiency syndrome drug, 9-(R)-[2-(phosphonomethoxy)propyl]adenine (tenofovir), and related antiviral acyclic nucleoside phosphonates by CE using beta-CD as chiral selector

    Czech Academy of Sciences Publication Activity Database

    Šolínová, Veronika; Kašička, Václav; Sázelová, Petra; Holý, Antonín

    2009-01-01

    Roč. 30, č. 12 (2009), s. 2245-2254 ISSN 0173-0835 R&D Projects: GA ČR(CZ) GA203/06/1044; GA ČR(CZ) GA203/08/1428; GA AV ČR 1QS400550501; GA MŠk 1M0508 Institutional research plan: CEZ:AV0Z40550506 Keywords : antiviral drugs * capillary electrophoresis * enantioseparation Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 3.077, year: 2009

  17. Virological surveillance and antiviral resistance of human influenza virus in Argentina, 2005-2008 Vigilancia virológica y resistencia a los antivíricos del virus de la gripe humana en la Argentina, 2005-2008

    Directory of Open Access Journals (Sweden)

    Andrea Pontoriero

    2011-12-01

    Full Text Available OBJECTIVE: To describe the virological characteristics of the influenza strains circulating in Argentina in 2005-2008 and to assess the prevalence of antiviral resistance. METHODS: On the basis of their geographical spread and prevalence, influenza A and B isolates grown in Madin-Darby canine kidney cells were selected after antigenic and genomic characterization to be analyzed for antiviral resistance by enzymatic assay and pyrosequencing. Amantadine susceptibility was evaluated by pyrosequencing for known resistance markers on 45 strains of influenza A. Susceptibility to oseltamivir and zanamivir was evaluated by enzymatic assay of 67 influenza A and 46 influenza B strains, some of which were further analyzed by sequencing the neuraminidase gene. RESULTS: Resistance to amantadine was observed only on A(H3N2 strains (29/33; all of them carried the mutation S31N in their M2 sequence. Oseltamivir resistance was observed in 12 (34.3% of the 35 A(H1N1 strains from 2008; all of them carried the mutation H275Y in their neuraminidase sequence. All these viruses remained sensitive to zanamivir. CONCLUSIONS: This study describes a high incidence of amantadine-resistant influenza A(H3N2 viruses since 2006 and an unprecedented increase in oseltamivir resistance detected only in influenza A(H1N1 viruses isolated in 2008. Influenza A and B viruses were more sensitive to oseltamivir than to zanamivir, and influenza A viruses were more sensitive to both neuraminidase inhibitors than the influenza B viruses. The national data generated and analyzed in this study may help increase knowledge about influenza antiviral drug resistance, which is a problem of global concern.OBJETIVO: Describir las características virológicas de las cepas de virus de la gripe que circulaban en la Argentina entre el 2005 y el 2008, y evaluar la prevalencia de la resistencia a los antivíricos. MÉTODOS: Según su diseminación geográfica y su prevalencia, se seleccionaron aislados

  18. Assessment of the antiviral properties of recombinant surfactant protein D against influenza B virus in vitro

    NARCIS (Netherlands)

    Hillaire, Marine L.B.; van Eijk, Martin; Vogelzang-van Trierum, Stella E; Nieuwkoop, Nella J; van Riel, Debby; Fouchier, Ron A M; Kuiken, Thijs; Osterhaus, Albert D.M.E.; Haagsman, Henk P.; Rimmelzwaan, Guus F

    2015-01-01

    The armamentarium of antiviral drugs against influenza viruses is limited. Furthermore, influenza viruses emerge that are resistant to existing antiviral drugs like the M2 and NA inhibitors. Therefore, there is an urgent need for the development of novel classes of antiviral drugs. Here we

  19. Self-assembled dopamine nanolayers wrapped carbon nanotubes as carbon-carbon bi-functional nanocatalyst for highly efficient oxygen reduction reaction and antiviral drug monitoring

    Science.gov (United States)

    Khalafallah, Diab; Akhtar, Naeem; Alothman, Othman Y.; Fouad, H.; Abdelrazek khalil, Khalil

    2017-09-01

    Oxygen reduction reaction (ORR) catalysts are the heart of eco-friendly energy resources particularly low temperature fuel cells. Although valuable efforts have been devoted to synthesize high performance catalysts for ORR, considerable challenges are extremely desirable in the development of energy technologies. Herein, we report a simple self-polymerization method to build a thin film of dopamine along the tubular nanostructures of multi-walled carbon nanotubes (CNT) in a weak alkaline solution. The dopamine@CNT hybrid (denoted as DA@CNT) reveals an enhanced electrocatalytic activity towards ORR with highly positive onset potential and cathodic current as a result of their outstanding features of longitudinal mesoporous structure, high surface area, and ornamentation of DA layers with nitrogen moieties, which enable fast electron transport and fully exposed electroactive sites. Impressively, the as-obtained hybrid afford remarkable electrochemical durability for prolonged test time of 60,000 s compared to benchmark Pt/C (20 wt%) catalyst. Furthermore, the developed DA@CNT electrode was successfully applied to access the quality of antiviral drug named Valacyclovir (VCR). The DA@CNT electrode shows enhanced sensing performance in terms of large linear range (3-75 nM), low limit of detection (2.55 nM) than CNT based electrode, indicating the effectiveness of the DA coating. Interestingly, the synergetic effect of nanostructured DA and CNT can significantly boost the electronic configuration and exposure level of active species for ORR and biomolecule recognition. Therefore, the existing carbon-based porous electrocatalyst may find numerous translational applications as attractive alternative to noble metals in polymer electrolyte membrane fuel cells and quality control assessment of pharmaceutical and therapeutic drugs.

  20. Antiviral effects of Psidium guajava Linn. (guava) tea on the growth of clinical isolated H1N1 viruses: its role in viral hemagglutination and neuraminidase inhibition.

    Science.gov (United States)

    Sriwilaijaroen, Nongluk; Fukumoto, Syuichi; Kumagai, Kenji; Hiramatsu, Hiroaki; Odagiri, Takato; Tashiro, Masato; Suzuki, Yasuo

    2012-05-01

    Rapid evolution of influenza RNA virus has resulted in limitation of vaccine effectiveness, increased emergence of drug-resistant viruses and occurrence of pandemics. A new effective antiviral is therefore needed for control of the highly mutative influenza virus. Teas prepared by the infusion method were tested for their anti-influenza activity against clinical influenza A (H1N1) isolates by a 19-h influenza growth inhibition assay with ST6Gal I-expressing MDCK cells (AX4 cells) using fluorogenic quantification and chromogenic visualization. Guava tea markedly inhibited the growth of A/Narita/1/2009 (amantadine-resistant pandemic 2009 strain) at an IC(50) of 0.05% and the growth of A/Yamaguchi/20/06 (sensitive strain) and A/Kitakyushu/10/06 (oseltamivir-resistant strain) at similar IC(50) values ranging from 0.24% to 0.42% in AX4 cells, being 3.4- to 5.4-fold more potent than green tea (IC(50) values: 0.27% for the 2009 pandemic strain and 0.91% to 1.44% for the seasonal strains). In contrast to both teas, oseltamivir carboxylate (OC) demonstrated high potency against the growth of A/Narita/1/09 (IC(50) of 3.83nM) and A/Yamaguchi/20/06 (IC(50) of 11.57nM) but not against that of A/Kitakyushu/10/06 bearing a His274-to-Tyr substitution (IC(50) of 15.97μM). Immunofluorescence analysis under a confocal microscope indicated that both teas inhibited the most susceptible A/Narita/1/2009 virus at the initial stage of virus infection. This is consistent with results of direct inhibition assays showing that both teas inhibited viral hemagglutination at concentrations comparable to their growth inhibition concentrations but inhibited sialidase activity at about 8-times higher concentrations. Guava tea shows promise to be efficacious for control of epidemic and pandemic influenza viruses including oseltamivir-resistant strains, and its broad target blockage makes it less likely to lead to emergence of viral resistance. Copyright © 2012 Elsevier B.V. All rights reserved.

  1. Antiviral activity of formyl peptide receptor 2 antagonists against influenza viruses.

    Science.gov (United States)

    Courtin, Noémie; Fotso, Aurélien Fotso; Fautrad, Pierre; Mas, Floriane; Alessi, Marie-Christine; Riteau, Béatrice

    2017-07-01

    Influenza viruses are one of the most important respiratory pathogens worldwide, causing both epidemic and pandemic infections. The aim of the study was to evaluate the effect of FPR2 antagonists PBP10 and BOC2 on influenza virus replication. We determined that these molecules exhibit antiviral effects against influenza A (H1N1, H3N2, H6N2) and B viruses. FPR2 antagonists used in combination with oseltamivir showed additive antiviral effects. Mechanistically, the antiviral effect of PBP10 and BOC2 is mediated through early inhibition of virus-induced ERK activation. Finally, our preclinical studies showed that FPR2 antagonists protected mice from lethal infections induced by influenza, both in a prophylactic and therapeutic manner. Thus, FPR2 antagonists might be explored for novel treatments against influenza. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. In silico study of rotavirus VP7 surface accessible conserved regions for antiviral drug/vaccine design.

    Directory of Open Access Journals (Sweden)

    Ambarnil Ghosh

    Full Text Available BACKGROUND: Rotaviral diarrhoea kills about half a million children annually in developing countries and accounts for one third of diarrhea related hospitalizations. Drugs and vaccines against the rotavirus are handicapped, as in all viral diseases, by the rapid mutational changes that take place in the DNA and protein sequences rendering most of these ineffective. As of now only two vaccines are licensed and approved by the WHO (World Health Organization, but display reduced efficiencies in the underdeveloped countries where the disease is more prevalent. We approached this issue by trying to identify regions of surface exposed conserved segments on the surface glycoproteins of the virion, which may then be targeted by specific peptide vaccines. We had developed a bioinformatics protocol for these kinds of problems with reference to the influenza neuraminidase protein, which we have refined and expanded to analyze the rotavirus issue. RESULTS: Our analysis of 433 VP7 (Viral Protein 7 from rotavirus surface protein sequences across 17 subtypes encompassing mammalian hosts using a 20D Graphical Representation and Numerical Characterization method, identified four possible highly conserved peptide segments. Solvent accessibility prediction servers were used to identify that these are predominantly surface situated. These regions analyzed through selected epitope prediction servers for their epitopic properties towards possible T-cell and B-cell activation showed good results as epitopic candidates (only dry lab confirmation. CONCLUSIONS: The main reasons for the development of alternative vaccine strategies for the rotavirus are the failure of current vaccines and high production costs that inhibit their application in developing countries. We expect that it would be possible to use the protein surface exposed regions identified in our study as targets for peptide vaccines and drug designs for stable immunity against divergent strains of the

  3. Oseltamivir Pharmacokinetics and Clinical Experience in Neonates and Infants during an Outbreak of H1N1 Influenza A Virus Infection in a Neonatal Intensive Care Unit

    Science.gov (United States)

    Nika, Angela; Tsagris, Vasileios; Kapetanakis, Ioannis; Maltezou, Helena C.; Kafetzis, Dimitris A.; Tsolia, Maria N.

    2012-01-01

    Detailed oseltamivir pharmacokinetics have yet to be reported in neonates and infants; this group is at high risk of serious influenza-associated complications. Extrapolation of doses from older patients is complicated by rapid organ and drug-metabolizing enzyme maturation. A pharmacokinetic study has been conducted during an influenza A(H1N1) outbreak in a neonatal intensive care unit. Each included patient provided 4 samples for oseltamivir and 4 samples for its active metabolite oseltamivir carboxylate. A population pharmacokinetic model was developed with NONMEM. Allometric weight scaling and maturation functions were added a priori to scale for size and age based on literature values. Nine neonates and infants were recruited. A physiologically parameterized pharmacokinetic model predicted typical day 1 area under the curve (AUC0-12) values of 1,966 and 2,484 μg · h/liter for neonates and infants of ≤37 weeks of postmenstrual age (PMA) and >37 weeks of PMA treated with 1 mg/kg of body weight and 2 mg/kg, respectively. The corresponding steady-state AUC0-12 values were 3,670 and 4,559 μg · h/liter. Premature neonates treated with 1 mg/kg and term babies treated with 2 mg/kg should have average oseltamivir carboxylate concentrations in a range similar to that for adults treated with 75 mg, corresponding to >200-fold above the half-maximal inhibitory concentration (IC50) value for influenza A(H1N1) from the start of therapy. PMID:22564835

  4. Intra- and inter-pandemic variations of antiviral, antibiotics and decongestants in wastewater treatment plants and receiving rivers.

    Directory of Open Access Journals (Sweden)

    Andrew C Singer

    Full Text Available The concentration of eleven antibiotics (trimethoprim, oxytetracycline, ciprofloxacin, azithromycin, cefotaxime, doxycycline, sulfamethoxazole, erythromycin, clarithromycin, ofloxacin, norfloxacin, three decongestants (naphazoline, oxymetazoline, xylometazoline and the antiviral drug oseltamivir's active metabolite, oseltamivir carboxylate (OC, were measured weekly at 21 locations within the River Thames catchment in England during the month of November 2009, the autumnal peak of the influenza A[H1N1]pdm09 pandemic. The aim was to quantify the pharmaceutical response to the pandemic and compare this to drug use during the late pandemic (March 2010 and the inter-pandemic periods (May 2011. A large and small wastewater treatment plant (WWTP were sampled in November 2009 to understand the differential fate of the analytes in the two WWTPs prior to their entry in the receiving river and to estimate drug users using a wastewater epidemiology approach. Mean hourly OC concentrations in the small and large WWTP's influent were 208 and 350 ng/L (max, 2070 and 550 ng/L, respectively. Erythromycin was the most concentrated antibiotic measured in Benson and Oxford WWTPs influent (max=6,870 and 2,930 ng/L, respectively. Napthazoline and oxymetazoline were the most frequently detected and concentrated decongestant in the Benson WWTP influent (1650 and 67 ng/L and effluent (696 and 307 ng/L, respectively, but were below detection in the Oxford WWTP. OC was found in 73% of November 2009's weekly river samples (max=193 ng/L, but only in 5% and 0% of the late- and inter-pandemic river samples, respectively. The mean river concentration of each antibiotic during the pandemic largely fell between 17-74 ng/L, with clarithromycin (max=292 ng/L and erythromycin (max=448 ng/L yielding the highest single measure. In general, the concentration and frequency of detecting antibiotics in the river increased during the pandemic. OC was uniquely well-suited for the wastewater

  5. Conformational Analysis, Molecular Structure and Solid State Simulation of the Antiviral Drug Acyclovir (Zovirax Using Density Functional Theory Methods

    Directory of Open Access Journals (Sweden)

    Margarita Clara Alvarez-Ros

    2014-06-01

    Full Text Available The five tautomers of the drug acyclovir (ACV were determined and optimised at the MP2 and B3LYP quantum chemical levels of theory. The stability of the tautomers was correlated with different parameters. On the most stable tautomer N1 was carried out a comprehensive conformational analysis, and the whole conformational parameters (R, β, Φ, φ1, φ2, φ3, φ4, φ5 were studied as well as the NBO Natural atomic charges. The calculations were carried out with full relaxation of all geometrical parameters. The search located at least 78 stable structures within 8.5 kcal/mol electronic energy range of the global minimum, and classified in two groups according to the positive or negative value of the torsional angle j1. In the nitrogen atoms and in the O2' and O5' oxygen atoms of the most stable conformer appear a higher reactivity than in the natural nucleoside deoxyguanosine. The solid state was simulated through a dimer and tetramer forms and the structural parameters were compared with the X-ray crystal data available. Several general conclusions were emphasized.

  6. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society-USA Panel.

    Science.gov (United States)

    Günthard, Huldrych F; Saag, Michael S; Benson, Constance A; del Rio, Carlos; Eron, Joseph J; Gallant, Joel E; Hoy, Jennifer F; Mugavero, Michael J; Sax, Paul E; Thompson, Melanie A; Gandhi, Rajesh T; Landovitz, Raphael J; Smith, Davey M; Jacobsen, Donna M; Volberding, Paul A

    2016-07-12

    New data and therapeutic options warrant updated recommendations for the use of antiretroviral drugs (ARVs) to treat or to prevent HIV infection in adults. To provide updated recommendations for the use of antiretroviral therapy in adults (aged ≥18 years) with established HIV infection, including when to start treatment, initial regimens, and changing regimens, along with recommendations for using ARVs for preventing HIV among those at risk, including preexposure and postexposure prophylaxis. A panel of experts in HIV research and patient care convened by the International Antiviral Society-USA reviewed data published in peer-reviewed journals, presented by regulatory agencies, or presented as conference abstracts at peer-reviewed scientific conferences since the 2014 report, for new data or evidence that would change previous recommendations or their ratings. Comprehensive literature searches were conducted in the PubMed and EMBASE databases through April 2016. Recommendations were by consensus, and each recommendation was rated by strength and quality of the evidence. Newer data support the widely accepted recommendation that antiretroviral therapy should be started in all individuals with HIV infection with detectable viremia regardless of CD4 cell count. Recommended optimal initial regimens for most patients are 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (InSTI). Other effective regimens include nonnucleoside reverse transcriptase inhibitors or boosted protease inhibitors with 2 NRTIs. Recommendations for special populations and in the settings of opportunistic infections and concomitant conditions are provided. Reasons for switching therapy include convenience, tolerability, simplification, anticipation of potential new drug interactions, pregnancy or plans for pregnancy, elimination of food restrictions, virologic failure, or drug toxicities. Laboratory assessments are recommended before treatment, and

  7. Mathematical Modeling of Hepatitis C Prevalence Reduction with Antiviral Treatment Scale-Up in Persons Who Inject Drugs in Metropolitan Chicago.

    Science.gov (United States)

    Echevarria, Desarae; Gutfraind, Alexander; Boodram, Basmattee; Major, Marian; Del Valle, Sara; Cotler, Scott J; Dahari, Harel

    2015-01-01

    New direct-acting antivirals (DAAs) provide an opportunity to combat hepatitis C virus (HCV) infection in persons who inject drugs (PWID). Here we use a mathematical model to predict the impact of a DAA-treatment scale-up on HCV prevalence among PWID and the estimated cost in metropolitan Chicago. To estimate the HCV antibody and HCV-RNA (chronic infection) prevalence among the metropolitan Chicago PWID population, we used empirical data from three large epidemiological studies. Cost of DAAs is assumed $50,000 per person. Approximately 32,000 PWID reside in metropolitan Chicago with an estimated HCV-RNA prevalence of 47% or 15,040 cases. Approximately 22,000 PWID (69% of the total PWID population) attend harm reduction (HR) programs, such as syringe exchange programs, and have an estimated HCV-RNA prevalence of 30%. There are about 11,000 young PWID (<30 years old) with an estimated HCV-RNA prevalence of 10% (PWID in these two subpopulations overlap). The model suggests that the following treatment scale-up is needed to reduce the baseline HCV-RNA prevalence by one-half over 10 years of treatment [cost per year, min-max in millions]: 35 per 1,000 [$50-$77] in the overall PWID population, 19 per 1,000 [$20-$26] for persons in HR programs, and 5 per 1,000 [$3-$4] for young PWID. Treatment scale-up could dramatically reduce the prevalence of chronic HCV infection among PWID in Chicago, who are the main reservoir for on-going HCV transmission. Focusing treatment on PWID attending HR programs and/or young PWID could have a significant impact on HCV prevalence in these subpopulations at an attainable cost.

  8. Preparation of molecularly imprinted solid-phase microextraction fiber for the selective removal and extraction of the antiviral drug abacavir in environmental and biological matrices

    International Nuclear Information System (INIS)

    Terzopoulou, Zoi; Papageorgiou, Myrsini; Kyzas, George Z.; Bikiaris, Dimitrios N.; Lambropoulou, Dimitra A.

    2016-01-01

    In the present study, a molecularly imprinted solid-phase microextraction fiber (MIP-SPME f ) was synthesized and applied for the selective removal and extraction of the antiviral drug, abacavir (ABA). Morphology and structure characterization of fibers were performed by scanning electron microscopy and Fourier transform infrared spectra, respectively. The effects on the adsorption behavior of the process parameters were studied and the equilibrium data were fitted by the Langmuir, Freundlich and Langmuir-Freundlich models. The maximum adsorption capability (Q max ) was determined by Langmuir- Freundlich model and was 149 mg/g for MIP-SPME f . In the next step, SPME methodology followed by liquid desorption and liquid chromatography with mass spectrometry (LC/MS) has been developed and evaluated for the determination of the target compound in environmental and biological matrices (surface waters, wastewaters and urine). Parameters that could influence SPME efficiency were investigated. Then, optimization of stirring speed, extraction time and salt content was carried out by using a central composite design (CCD) and response surface methodology (RSM). A quadratic model between dependent and independent variables was built. Under the optimum conditions (extraction time 40 min, stirring rate 650 rpm and salt content 0.3% NaCl w/v) the validated method presented a high sensitivity and selectivity with LODs and LOQs in the range of 10.1–13.6 and 33.3–43.9 ng/L, respectively. The developed method was successfully applied to the analysis of ABA in real samples. The percentage extraction efficiency ranged from 88 to 99% revealing good accuracy and absence of matrix effects. - Highlights: • Preparation of a novel SPME MIP fiber with remarkable recognition properties. • Selective removal and extraction of abacavir from environmental & biological media. • Detailed adsorbent characterization and adsorption studies. • Successful application of synthesized MIPs

  9. Mathematical Modeling of Hepatitis C Prevalence Reduction with Antiviral Treatment Scale-Up in Persons Who Inject Drugs in Metropolitan Chicago.

    Directory of Open Access Journals (Sweden)

    Desarae Echevarria

    Full Text Available New direct-acting antivirals (DAAs provide an opportunity to combat hepatitis C virus (HCV infection in persons who inject drugs (PWID. Here we use a mathematical model to predict the impact of a DAA-treatment scale-up on HCV prevalence among PWID and the estimated cost in metropolitan Chicago.To estimate the HCV antibody and HCV-RNA (chronic infection prevalence among the metropolitan Chicago PWID population, we used empirical data from three large epidemiological studies. Cost of DAAs is assumed $50,000 per person.Approximately 32,000 PWID reside in metropolitan Chicago with an estimated HCV-RNA prevalence of 47% or 15,040 cases. Approximately 22,000 PWID (69% of the total PWID population attend harm reduction (HR programs, such as syringe exchange programs, and have an estimated HCV-RNA prevalence of 30%. There are about 11,000 young PWID (<30 years old with an estimated HCV-RNA prevalence of 10% (PWID in these two subpopulations overlap. The model suggests that the following treatment scale-up is needed to reduce the baseline HCV-RNA prevalence by one-half over 10 years of treatment [cost per year, min-max in millions]: 35 per 1,000 [$50-$77] in the overall PWID population, 19 per 1,000 [$20-$26] for persons in HR programs, and 5 per 1,000 [$3-$4] for young PWID.Treatment scale-up could dramatically reduce the prevalence of chronic HCV infection among PWID in Chicago, who are the main reservoir for on-going HCV transmission. Focusing treatment on PWID attending HR programs and/or young PWID could have a significant impact on HCV prevalence in these subpopulations at an attainable cost.

  10. A practical and azide-free synthetic approach to oseltamivir from diethyl D-tartrate.

    Science.gov (United States)

    Weng, Jiang; Li, Yong-Bo; Wang, Rui-Bin; Li, Feng-Quan; Liu, Can; Chan, Albert S C; Lu, Gui

    2010-05-07

    A short and practical synthesis of oseltamivir was accomplished in 11 steps from inexpensive and abundant diethyl D-tartrate starting material. This azide-free route featured an asymmetric aza-Henry reaction and a domino nitro-Michael/Horner-Wadsworth-Emmons (HWE) reaction as the key steps to construct the relevant cyclohexene ring of the product, which provided an economical and practical alternative for the synthesis of oseltamivir.

  11. Seasonal Flu and Staph Infection

    Science.gov (United States)

    ... What are Flu Antiviral Drugs Antiviral Drug Resistance Mixing Oseltamivir Capsules For Children What to do if ... PowerPoint file Microsoft Word file Microsoft Excel file Audio/Video file Apple Quicktime file RealPlayer file Text ...

  12. Influenza Prevention: Information for Travelers

    Science.gov (United States)

    ... What are Flu Antiviral Drugs Antiviral Drug Resistance Mixing Oseltamivir Capsules For Children What to do if ... PowerPoint file Microsoft Word file Microsoft Excel file Audio/Video file Apple Quicktime file RealPlayer file Text ...

  13. Caring for Someone Sick (Flu)

    Science.gov (United States)

    ... What are Flu Antiviral Drugs Antiviral Drug Resistance Mixing Oseltamivir Capsules For Children What to do if ... PowerPoint file Microsoft Word file Microsoft Excel file Audio/Video file Apple Quicktime file RealPlayer file Text ...

  14. Guillain-Barré Syndrome (GBS) and Flu Vaccine

    Science.gov (United States)

    ... What are Flu Antiviral Drugs Antiviral Drug Resistance Mixing Oseltamivir Capsules For Children What to do if ... PowerPoint file Microsoft Word file Microsoft Excel file Audio/Video file Apple Quicktime file RealPlayer file Text ...

  15. Flu Widget

    Science.gov (United States)

    ... What are Flu Antiviral Drugs Antiviral Drug Resistance Mixing Oseltamivir Capsules For Children What to do if ... PowerPoint file Microsoft Word file Microsoft Excel file Audio/Video file Apple Quicktime file RealPlayer file Text ...

  16. Pregnant Women and Influenza (Flu)

    Science.gov (United States)

    ... What are Flu Antiviral Drugs Antiviral Drug Resistance Mixing Oseltamivir Capsules For Children What to do if ... PowerPoint file Microsoft Word file Microsoft Excel file Audio/Video file Apple Quicktime file RealPlayer file Text ...

  17. Diagnosing Flu

    Science.gov (United States)

    ... What are Flu Antiviral Drugs Antiviral Drug Resistance Mixing Oseltamivir Capsules For Children What to do if ... PowerPoint file Microsoft Word file Microsoft Excel file Audio/Video file Apple Quicktime file RealPlayer file Text ...

  18. Flu & You: Preventive Steps

    Science.gov (United States)

    ... What are Flu Antiviral Drugs Antiviral Drug Resistance Mixing Oseltamivir Capsules For Children What to do if ... PowerPoint file Microsoft Word file Microsoft Excel file Audio/Video file Apple Quicktime file RealPlayer file Text ...

  19. Preventing the Flu: Good Health Habits Can Help Stop Germs

    Science.gov (United States)

    ... What are Flu Antiviral Drugs Antiviral Drug Resistance Mixing Oseltamivir Capsules For Children What to do if ... PowerPoint file Microsoft Word file Microsoft Excel file Audio/Video file Apple Quicktime file RealPlayer file Text ...

  20. Influenza vaccination and antiviral therapy: is there a role for concurrent administration in the institutionalised elderly?

    Science.gov (United States)

    Drinka, Paul J

    2003-01-01

    Influenza vaccination is estimated to be 50-68% efficacious in preventing pneumonia, hospitalisation or death in nursing home residents. Large culture-proven outbreaks may occur despite high resident vaccination rates. There is, therefore, a significant role for concurrent administration of influenza vaccination and antiviral therapy. The use of antiviral treatment and chemoprophylaxis requires community reporting of viral isolates, and contingency plans for rapid case identification and application of antiviral therapy. Clinicians must react quickly to control a highly infectious seasonal pathogen that may strike as an explosive outbreak. This situation is unique in geriatric practice. Current antiviral treatment should be administered within 48 hours of symptom onset, and is more efficacious if administered within 12 hours. In the case of an explosive institutional outbreak, a 1-day delay in prophylaxis may allow infection of many residents with a potentially fatal illness. Influenza must be differentiated from other respiratory viruses or syndromes. Grouped rapid diagnostic tests can aid laboratory confirmation. Antiviral agents include the M(2) inhibitors, amantadine and rimantadine, active against influenza A, and the neuraminidase inhibitors, zanamivir and oseltamivir, active against influenza A and B. In our experience, influenza B illness is as severe as influenza A. All agents have similar efficacy as treatment and prophylaxis against sensitive strains. When M(2) inhibitors are used simultaneously within an enclosed space (i.e. household or nursing home) as both treatment and prophylaxis, resistant strains may emerge that limit prophylactic efficacy. When M(2) inhibitors are administered to suspected cases (residents or staff) in institutions, precautions against secretion are especially important to diminish the risk of transmission of resistant virus. Rimantadine has been shown to have significantly fewer CNS adverse events compared with amantadine

  1. Preparation of molecularly imprinted solid-phase microextraction fiber for the selective removal and extraction of the antiviral drug abacavir in environmental and biological matrices

    Energy Technology Data Exchange (ETDEWEB)

    Terzopoulou, Zoi [Laboratory of Polymer Chemistry and Technology, Department of Chemistry, Aristotle University of Thessaloniki, GR-541 24, Thessaloniki (Greece); Papageorgiou, Myrsini [Laboratory of Environmental Pollution Control, Department of Chemistry, Aristotle University of Thessaloniki, GR–541 24, Thessaloniki (Greece); Kyzas, George Z.; Bikiaris, Dimitrios N. [Laboratory of Polymer Chemistry and Technology, Department of Chemistry, Aristotle University of Thessaloniki, GR-541 24, Thessaloniki (Greece); Lambropoulou, Dimitra A., E-mail: dlambro@chem.auth.gr [Laboratory of Environmental Pollution Control, Department of Chemistry, Aristotle University of Thessaloniki, GR–541 24, Thessaloniki (Greece)

    2016-03-24

    In the present study, a molecularly imprinted solid-phase microextraction fiber (MIP-SPME{sub f}) was synthesized and applied for the selective removal and extraction of the antiviral drug, abacavir (ABA). Morphology and structure characterization of fibers were performed by scanning electron microscopy and Fourier transform infrared spectra, respectively. The effects on the adsorption behavior of the process parameters were studied and the equilibrium data were fitted by the Langmuir, Freundlich and Langmuir-Freundlich models. The maximum adsorption capability (Q{sub max}) was determined by Langmuir- Freundlich model and was 149 mg/g for MIP-SPME{sub f}. In the next step, SPME methodology followed by liquid desorption and liquid chromatography with mass spectrometry (LC/MS) has been developed and evaluated for the determination of the target compound in environmental and biological matrices (surface waters, wastewaters and urine). Parameters that could influence SPME efficiency were investigated. Then, optimization of stirring speed, extraction time and salt content was carried out by using a central composite design (CCD) and response surface methodology (RSM). A quadratic model between dependent and independent variables was built. Under the optimum conditions (extraction time 40 min, stirring rate 650 rpm and salt content 0.3% NaCl w/v) the validated method presented a high sensitivity and selectivity with LODs and LOQs in the range of 10.1–13.6 and 33.3–43.9 ng/L, respectively. The developed method was successfully applied to the analysis of ABA in real samples. The percentage extraction efficiency ranged from 88 to 99% revealing good accuracy and absence of matrix effects. - Highlights: • Preparation of a novel SPME MIP fiber with remarkable recognition properties. • Selective removal and extraction of abacavir from environmental & biological media. • Detailed adsorbent characterization and adsorption studies. • Successful application of

  2. Oseltamivir Use Among Children and Adults Hospitalized With Community-Acquired Pneumonia.

    Science.gov (United States)

    Oboho, Ikwo K; Bramley, Anna; Finelli, Lyn; Fry, Alicia; Ampofo, Krow; Arnold, Sandra R; Self, Wesley H; Williams, Derek J; Courtney, D Mark; Zhu, Yuwei; Anderson, Evan J; Grijalva, Carlos G; McCullers, Jonathan A; Wunderink, Richard G; Pavia, Andrew T; Edwards, Kathryn M; Jain, Seema

    2017-01-01

    Data on oseltamivir treatment among hospitalized community-acquired pneumonia (CAP) patients are limited. Patients hospitalized with CAP at 6 hospitals during the 2010-2012 influenza seasons were included. We assessed factors associated with oseltamivir treatment using logistic regression. Oseltamivir treatment was provided to 89 of 1627 (5%) children (<18 years) and 143 of 1051 (14%) adults. Among those with positive clinician-ordered influenza tests, 39 of 61 (64%) children and 37 of 48 (77%) adults received oseltamivir. Among children, oseltamivir treatment was associated with hospital A (adjusted odds ratio [aOR], 2.76; 95% confidence interval [CI], 1.36-4.88), clinician-ordered testing performed (aOR, 2.44; 95% CI, 1.47-5.19), intensive care unit (ICU) admission (aOR, 2.09; 95% CI, 1.27-3.45), and age ≥2 years (aOR, 1.43; 95% CI, 1.16-1.76). Among adults, oseltamivir treatment was associated with clinician-ordered testing performed (aOR, 8.38; 95% CI, 4.64-15.12), hospitals D and E (aOR, 3.46-5.11; 95% CI, 1.75-11.01), Hispanic ethnicity (aOR, 2.06; 95% CI, 1.18-3.59), and ICU admission (aOR, 2.05; 95% CI, 1.34-3.13). Among patients hospitalized with CAP during influenza season, oseltamivir treatment was moderate overall and associated with clinician-ordered testing, severe illness, and specific hospitals. Increased clinician education is needed to include influenza in the differential diagnosis for hospitalized CAP patients and to test and treat patients empirically if influenza is suspected. Published by Oxford University Press on behalf of Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  3. Analyses of nanoformulated antiretroviral drug charge, size, shape and content for uptake, drug release and antiviral activities in human monocyte-derived macrophages.

    Science.gov (United States)

    Nowacek, Ari S; Balkundi, Shantanu; McMillan, JoEllyn; Roy, Upal; Martinez-Skinner, Andrea; Mosley, R Lee; Kanmogne, Georgette; Kabanov, Alexander V; Bronich, Tatiana; Gendelman, Howard E

    2011-03-10

    Long-term antiretroviral therapy (ART) for human immunodeficiency virus type one (HIV-1) infection shows limitations in pharmacokinetics and biodistribution while inducing metabolic and cytotoxic aberrations. In turn, ART commonly requires complex dosing schedules and leads to the emergence of viral resistance and treatment failures. We posit that the development of nanoformulated ART could preclude such limitations and affect improved clinical outcomes. To this end, we wet-milled 20 nanoparticle formulations of crystalline indinavir, ritonavir, atazanavir, and efavirenz, collectively referred to as "nanoART," then assessed their performance using a range of physicochemical and biological tests. These tests were based on cell-nanoparticle interactions using monocyte-derived macrophages and their abilities to uptake and release nanoformulated drugs and affect viral replication. We demonstrate that physical characteristics such as particle size, surfactant coating, surface charge, and most importantly shape are predictors of cell uptake and antiretroviral efficacy. These studies bring this line of research a step closer to developing nanoART that can be used in the clinic to affect the course of HIV-1 infection. Copyright © 2010 Elsevier B.V. All rights reserved.

  4. DEVELOPMENT OF ANTIVIRAL AGENTS

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. DEVELOPMENT OF ANTIVIRAL AGENTS. Chandipura virus can be regarded as a model system to design and develop antiviral agents. These agents could be small molecules or RNA/PNA aptamers or Antisense RNA to speicific gene sequence in the viral genome.

  5. Self-interest versus group-interest in antiviral control

    NARCIS (Netherlands)

    Boven, M. van; Klinkenberg, D.; Pen, I.; Weissing, F.J.; Heesterbeek, J.A.P.

    2008-01-01

    Antiviral agents have been hailed to hold considerable promise for the treatment and prevention of emerging viral diseases like H5N1 avian influenza and SARS. However, antiviral drugs are not completely harmless, and the conditions under which individuals are willing to participate in a

  6. Self-interest versus group-interest in antiviral control

    NARCIS (Netherlands)

    van Boven, Michiel; Klinkenberg, Don; Pen, Ido; Weissing, Franz J.; Heesterbeek, Hans

    2008-01-01

    Antiviral agents have been hailed to hold considerable promise for the treatment and prevention of emerging viral diseases like H5N1 avian influenza and SARS. However, antiviral drugs are not completely harmless, and the conditions under which individuals are willing to participate in a large-scale

  7. Highlights of the 30th International Conference on Antiviral Research.

    Science.gov (United States)

    Andrei, Graciela; Carter, Kara; Janeba, Zlatko; Sampath, Aruna; Schang, Luis M; Tarbet, E Bart; Vere Hodge, R Anthony; Bray, Mike; Esté, José A

    2017-09-01

    The 30th International Conference on Antiviral Research (ICAR) was held in Atlanta, GA, USA from May 18 to 21, 2017. This report provides an account of award lectures, invited keynote addresses and oral presentations during the meeting. The 2017 Gertrude Elion Memorial Lecture Award by Michael Sofia highlighted one of the most important accomplishments in recent drug discovery in antiviral research, the identification of the hepatitis C virus direct-acting antiviral sofosbuvir and new alternatives to combat hepatitis B virus (HBV) infection. The Antonín Holý Lecture Award by David Chu on medicinal chemistry provided an overview of early developments of nucleoside analogs for the treatment of HIV and varicella zoster virus infection and how this knowledge serves to develop new drugs targeting HBV. Priscilla Yang gave the first ISAR Women in Science lecture. She reported on pharmacological validation of new antiviral targets for dengue, Zika and other flaviviruses. The William Prusoff Young Investigator Lecture Award by Maaike Everts described the Alabama Drug Discovery Alliance and the Antiviral Drug Discovery and Development Consortium, and how they are helping to accelerate the development of new antivirals. The 30th ICAR was a success in promoting new discoveries in antiviral drug development and research. The 31st ICAR will be held in Porto, Portugal, June 11-15, 2018. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Kinetic Study of the Alkaline Degradation of Oseltamivir Phosphate and Valacyclovir Hydrochloride using Validated Stability Indicating HPLC

    Directory of Open Access Journals (Sweden)

    Ramzia I. Al-Bagary

    2014-01-01

    Full Text Available Aqueous alkaline degradation was performed for oseltamivir phosphate (OP and valacyclovir hydrochloride (VA. Isocratic stability indicating the use of high-performance liquid chromatography (HPLC was presented for each drug in the presence of its degradation product. The separations were performed using the Nucleosil ODS column and a mobile phase consisting of phosphate buffer (pH = 7, acetonitrile, and methanol 50:25:25 (v/v/v for OP. For VA separation, a Nucleosil CN column using phosphate buffer (pH = 7 and methanol 85:15 (v/v was used as a mobile phase. Ultraviolet detection at 210 nm and 254 nm was used for OP and VA, respectively. The method showed high sensitivity concerning linearity, accuracy, and precision over the range 1-250 μg mL −1 for both drugs. The proposed method was used to determine the drug in its pharmaceutical formulation and to investigate the degradation kinetics of each drug's alkaline-stressed samples. The reactions were found to follow a first-order reaction. The activation energy could also be estimated. International Conference on Harmonisation guidelines were adopted for method validation.

  9. Combinatorial and sequential delivery of gemcitabine and oseltamivir phosphate from implantable poly(D,L-lactic-co-glycolic acid cylinders disables human pancreatic cancer cell survival

    Directory of Open Access Journals (Sweden)

    Allison Logan S

    2017-07-01

    Full Text Available Stephanie Allison Logan,1 Amanda J Brissenden,1 Myron R Szewczuk,2 Ronald J Neufeld1 1Department of Chemical Engineering, 2Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada Abstract: Combination therapies against multiple targets are currently being developed to prevent resistance to a single chemotherapeutic agent and to extirpate pre-existing resistance in heterogeneous cancer cells in tumors due to selective pressure from the single agent. Gemcitabine (GEM, a chemotherapeutic agent, is the current standard of care for patients with pancreatic cancer. Patients with pancreatic cancer receiving GEM have a low progression-free survival. Given the poor response rate to GEM, cancer cells are known to develop rapid resistance to this drug. Metronomic chemotherapy using combinatorial and sequential delivery systems are novel developmental approaches to disrupt tumor neovascularization, reduce systemic drug toxicity, and increase the sensitivity of chemotherapeutics in cancer. Here, implantable double-layered poly(D,L-lactic-co-glycolic acid (PLGA cylinders were engineered to sequentially release GEM in combination with oseltamivir phosphate (OP over an extended time. Double-layered PLGA cylindrical implants loaded with these active hydrophilic drugs were fabricated with minimal loss of drugs during the formulation, enabling extensive control of drug loading and establishing uniform drug distribution throughout the polymer matrix. OP is used in the formulation because of its anticancer drug properties targeting mammalian neuraminidase 1 (Neu1 involved in multistage tumorigenesis. OP and GEM encapsulated in inner/outer GEMin/OPout or OPin/GEMout implantable PLGA double-layered cylinders displayed sustained near linear release over 30 days. OP and GEM released from the double-layered cylinders effectively reduced cell viability in pancreatic cancer cell line PANC1 and its GEM-resistant variant for up to 15

  10. Antibody administration in experimental influenza increases survival and enhances the effect of oseltamivir

    DEFF Research Database (Denmark)

    Pourroy, Brit Naldahl Jessen; Kolmos, Hans Jørn; Nielsen, Lars Peter

    2012-01-01

    and treatment of a number of infectious diseases. In this experimental study anti-influenza antibodies were passively administrated to mice, subsequently they were infected with influenza virus and treated with oseltamivir. The aim was to investigate, if anti-influenza antibodies influenced the out come...... be considered in the in control of influenza....

  11. Outcomes of Oseltamivir Treatment for H1N1 Infection During Pregnancy: A Retrospective Study

    Directory of Open Access Journals (Sweden)

    Nermin Akdemir

    2011-04-01

    CONCLUSION: In this retrospective, study, we found that, H1N1 infection during pregnancy has a good prognosis and without complication for maternal health. Although oseltamivir therapy is safe in pregnant women, it can be associated with cardiac structural cardiac malformations in H1N1 infected pregnancy newborns

  12. Oseltamivir analogues bearing N-substituted guanidines as potent neuraminidase inhibitors

    NARCIS (Netherlands)

    Mooney, Caitlin A.; Johnson, Stuart A.; 'T Hart, Peter; Quarles Van Ufford, Linda; De Haan, Cornelis A M; Moret, Ed E.; Martin, Nathaniel I.

    2014-01-01

    A series of oseltamivir analogues bearing an N-substituted guanidine unit were prepared and evaluated as inhibitors of neuraminidases from four strains of influenza the two most potent analogues identified contain relatively small N-guanidine substituents (N-methyl and N-hydroxyl) and display

  13. Prolonged tenofovir treatment of macaques infected with K65R reverse transcriptase mutants of SIV results in the development of antiviral immune responses that control virus replication after drug withdrawal

    Directory of Open Access Journals (Sweden)

    Van Rompay Koen K A

    2012-07-01

    Full Text Available Abstract Background We reported previously that while prolonged tenofovir monotherapy of macaques infected with virulent simian immunodeficiency virus (SIV resulted invariably in the emergence of viral mutants with reduced in vitro drug susceptibility and a K65R mutation in reverse transcriptase, some animals controlled virus replication for years. Transient CD8+ cell depletion or short-term tenofovir interruption within 1 to 5 years of treatment demonstrated that a combination of CD8+ cell-mediated immune responses and continued tenofovir therapy was required for sustained suppression of viremia. We report here follow-up data on 5 such animals that received tenofovir for 8 to 14 years. Results Although one animal had a gradual increase in viremia from 3 years onwards, the other 4 tenofovir-treated animals maintained undetectable viremia with occasional viral blips (≤ 300 RNA copies/ml plasma. When tenofovir was withdrawn after 8 to 10 years from three animals with undetectable viremia, the pattern of occasional episodes of low viremia (≤ 3600 RNA/ml plasma continued throughout the 10-month follow-up period. These animals had low virus levels in lymphoid tissues, and evidence of multiple SIV-specific immune responses. Conclusion Under certain conditions (i.e., prolonged antiviral therapy initiated early after infection; viral mutants with reduced drug susceptibility a virus-host balance characterized by strong immunologic control of virus replication can be achieved. Although further research is needed to translate these findings into clinical applications, these observations provide hope for a functional cure of HIV infection via immunotherapeutic strategies that boost antiviral immunity and reduce the need for continuous antiretroviral therapy.

  14. The antiviral drug tenofovir, an inhibitor of Pannexin-1-mediated ATP release, prevents liver and skin fibrosis by downregulating adenosine levels in the liver and skin.

    Directory of Open Access Journals (Sweden)

    Jessica L Feig

    Full Text Available Fibrosing diseases are a leading cause of morbidity and mortality worldwide and, therefore, there is a need for safe and effective antifibrotic therapies. Adenosine, generated extracellularly by the dephosphorylation of adenine nucleotides, ligates specific receptors which play a critical role in development of hepatic and dermal fibrosis. Results of recent clinical trials indicate that tenofovir, a widely used antiviral agent, reverses hepatic fibrosis/cirrhosis in patients with chronic hepatitis B infection. Belonging to the class of acyclic nucleoside phosphonates, tenofovir is an analogue of AMP. We tested the hypothesis that tenofovir has direct antifibrotic effects in vivo by interfering with adenosine pathways of fibrosis using two distinct models of adenosine and A2AR-mediated fibrosis.Thioacetamide (100mg/kg IP-treated mice were treated with vehicle, or tenofovir (75mg/kg, SubQ (n = 5-10. Bleomycin (0.25U, SubQ-treated mice were treated with vehicle or tenofovir (75mg/kg, IP (n = 5-10. Adenosine levels were determined by HPLC, and ATP release was quantitated as luciferase-dependent bioluminescence. Skin breaking strength was analysed and H&E and picrosirus red-stained slides were imaged. Pannexin-1expression was knocked down following retroviral-mediated expression of of Pannexin-1-specific or scrambled siRNA.Treatment of mice with tenofovir diminished adenosine release from the skin of bleomycin-treated mice and the liver of thioacetamide-treated mice, models of diffuse skin fibrosis and hepatic cirrhosis, respectively. More importantly, tenofovir treatment diminished skin and liver fibrosis in these models. Tenofovir diminished extracellular adenosine concentrations by inhibiting, in a dose-dependent fashion, cellular ATP release but not in cells lacking Pannexin-1.These studies suggest that tenofovir, a widely used antiviral agent, could be useful in the treatment of fibrosing diseases.

  15. Anti-viral properties and mode of action of standardized Echinacea purpurea extract against highly pathogenic avian Influenza virus (H5N1, H7N7 and swine-origin H1N1 (S-OIV

    Directory of Open Access Journals (Sweden)

    Schoop Roland

    2009-11-01

    Full Text Available Abstract Background Influenza virus (IV infections are a major threat to human welfare and animal health worldwide. Anti-viral therapy includes vaccines and a few anti-viral drugs. However vaccines are not always available in time, as demonstrated by the emergence of the new 2009 H1N1-type pandemic strain of swine origin (S-OIV in April 2009, and the acquisition of resistance to neuraminidase inhibitors such as Tamiflu® (oseltamivir is a potential problem. Therefore the prospects for the control of IV by existing anti-viral drugs are limited. As an alternative approach to the common anti-virals we studied in more detail a commercial standardized extract of the widely used herb Echinacea purpurea (Echinaforce®, EF in order to elucidate the nature of its anti-IV activity. Results Human H1N1-type IV, highly pathogenic avian IV (HPAIV of the H5- and H7-types, as well as swine origin IV (S-OIV, H1N1, were all inactivated in cell culture assays by the EF preparation at concentrations ranging from the recommended dose for oral consumption to several orders of magnitude lower. Detailed studies with the H5N1 HPAIV strain indicated that direct contact between EF and virus was required, prior to infection, in order to obtain maximum inhibition in virus replication. Hemagglutination assays showed that the extract inhibited the receptor binding activity of the virus, suggesting that the extract interferes with the viral entry into cells. In sequential passage studies under treatment in cell culture with the H5N1 virus no EF-resistant variants emerged, in contrast to Tamiflu®, which produced resistant viruses upon passaging. Furthermore, the Tamiflu®-resistant virus was just as susceptible to EF as the wild type virus. Conclusion As a result of these investigations, we believe that this standard Echinacea preparation, used at the recommended dose for oral consumption, could be a useful, readily available and affordable addition to existing control options

  16. Overview on the antiviral activities and mechanisms of marine polysaccharides from seaweeds.

    Science.gov (United States)

    Shi, Qimin; Wang, Anjian; Lu, Zhonghua; Qin, Chunjun; Hu, Jing; Yin, Jian

    2017-12-01

    Marine polysaccharides are attracting increasing attention in medical and pharmaceutical development because of their important biological properties. The seaweed polysaccharides have now become a rich resource of potential antiviral drugs due to their antiviral activities against various viruses. The structural diversity and complexity of marine polysaccharides and their derivatives contribute to their antiviral activities in different phases of many different viral infection processes. This review mainly introduces the different types of seaweed polysaccharides and their derivatives with potent antiviral activities. Moreover, the antiviral mechanisms and medical applications of certain marine polysaccharides from seaweeds are also demonstrated. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Antiviral Lead Compounds from Marine Sponges

    Directory of Open Access Journals (Sweden)

    Kenneth P. Minneman

    2010-10-01

    Full Text Available Marine sponges are currently one of the richest sources of pharmacologically active compounds found in the marine environment. These bioactive molecules are often secondary metabolites, whose main function is to enable and/or modulate cellular communication and defense. They are usually produced by functional enzyme clusters in sponges and/or their associated symbiotic microorganisms. Natural product lead compounds from sponges have often been found to be promising pharmaceutical agents. Several of them have successfully been approved as antiviral agents for clinical use or have been advanced to the late stages of clinical trials. Most of these drugs are used for the treatment of human immunodeficiency virus (HIV and herpes simplex virus (HSV. The most important antiviral lead of marine origin reported thus far is nucleoside Ara-A (vidarabine isolated from sponge Tethya crypta. It inhibits viral DNA polymerase and DNA synthesis of herpes, vaccinica and varicella zoster viruses. However due to the discovery of new types of viruses and emergence of drug resistant strains, it is necessary to develop new antiviral lead compounds continuously. Several sponge derived antiviral lead compounds which are hopedto be developed as future drugs are discussed in this review. Supply problems are usually the major bottleneck to the development of these compounds as drugs during clinical trials. However advances in the field of metagenomics and high throughput microbial cultivation has raised the possibility that these techniques could lead to the cost-effective large scale production of such compounds. Perspectives on biotechnological methods with respect to marine drug development are also discussed.

  18. Antiviral lead compounds from marine sponges.

    Science.gov (United States)

    Sagar, Sunil; Kaur, Mandeep; Minneman, Kenneth P

    2010-10-11

    Marine sponges are currently one of the richest sources of pharmacologically active compounds found in the marine environment. These bioactive molecules are often secondary metabolites, whose main function is to enable and/or modulate cellular communication and defense. They are usually produced by functional enzyme clusters in sponges and/or their associated symbiotic microorganisms. Natural product lead compounds from sponges have often been found to be promising pharmaceutical agents. Several of them have successfully been approved as antiviral agents for clinical use or have been advanced to the late stages of clinical trials. Most of these drugs are used for the treatment of human immunodeficiency virus (HIV) and herpes simplex virus (HSV). The most important antiviral lead of marine origin reported thus far is nucleoside Ara-A (vidarabine) isolated from sponge Tethya crypta. It inhibits viral DNA polymerase and DNA synthesis of herpes, vaccinica and varicella zoster viruses. However due to the discovery of new types of viruses and emergence of drug resistant strains, it is necessary to develop new antiviral lead compounds continuously. Several sponge derived antiviral lead compounds which are hoped to be developed as future drugs are discussed in this review. Supply problems are usually the major bottleneck to the development of these compounds as drugs during clinical trials. However advances in the field of metagenomics and high throughput microbial cultivation has raised the possibility that these techniques could lead to the cost-effective large scale production of such compounds. Perspectives on biotechnological methods with respect to marine drug development are also discussed.

  19. Antiviral lead compounds from marine sponges

    KAUST Repository

    Sagar, Sunil

    2010-10-11

    Marine sponges are currently one of the richest sources of pharmacologically active compounds found in the marine environment. These bioactive molecules are often secondary metabolites, whose main function is to enable and/or modulate cellular communication and defense. They are usually produced by functional enzyme clusters in sponges and/or their associated symbiotic microorganisms. Natural product lead compounds from sponges have often been found to be promising pharmaceutical agents. Several of them have successfully been approved as antiviral agents for clinical use or have been advanced to the late stages of clinical trials. Most of these drugs are used for the treatment of human immunodeficiency virus (HIV) and herpes simplex virus (HSV). The most important antiviral lead of marine origin reported thus far is nucleoside Ara-A (vidarabine) isolated from sponge Tethya crypta. It inhibits viral DNA polymerase and DNA synthesis of herpes, vaccinica and varicella zoster viruses. However due to the discovery of new types of viruses and emergence of drug resistant strains, it is necessary to develop new antiviral lead compounds continuously. Several sponge derived antiviral lead compounds which are hopedto be developed as future drugs are discussed in this review. Supply problems are usually the major bottleneck to the development of these compounds as drugs during clinical trials. However advances in the field of metagenomics and high throughput microbial cultivation has raised the possibility that these techniques could lead to the cost-effective large scale production of such compounds. Perspectives on biotechnological methods with respect to marine drug development are also discussed. 2010 by the authors; licensee MDPI.

  20. Antiviral therapy and outcomes of patients with pneumonia caused by influenza A pandemic (H1N1 virus.

    Directory of Open Access Journals (Sweden)

    Shi-gui Yang

    Full Text Available BACKGROUND: There is limited data on the clinical outcome of patients with pandemic H1N1 (pH1N1 pneumonia who received oseltamivir treatment, especially when the treatment was administered more than 48 hours after symptom onset. METHODS: During the pandemic in 2009, a cohort of pH1N1 influenza pneumonia was built in China, and their clinical information was collected systematically, and analyzed with Cox models. RESULTS: 920 adults and 541 children with pneumonia who didn't receive corticosteroids were analyzed. In-hospital mortality was higher in adults who did not receive antiviral therapy (18.2% than those with who received oseltamivir ≤ 2 days (2.9%, between 2-5 days (4.6% and >5 days after illness onset (4.9%, p5 days, respectively. For males patients, aged ≥ 14 years and baseline PaO(2/FiO(23.8 mg/kg/d did not improve clinical outcome (mortality, higher dose 2.5% vs standard dose 2.8%, p>0.05. CONCLUSIONS: Antiviral therapy might reduce mortality of patients with pH1N1 pneumonia, even when initiated more than 48 hours after onset of illness. Greater protective effects might be in males, patients aged 14-60 years, and patients with PaO(2/FiO(2<200.

  1. Tracking oseltamivir-resistance in New Zealand influenza viruses during a medicine reclassification in 2007, a resistant-virus importation in 2008 and the 2009 pandemic

    Directory of Open Access Journals (Sweden)

    Q Sue Huang

    2012-10-01

    Full Text Available Introduction: Oseltamivir (Tamiflu® is an important pharmaceutical intervention against the influenza virus. The importance of surveillance for resistance to oseltamivir has been highlighted by two global events: the emergence of an oseltamivir-resistant seasonal influenza A(H1N1 virus in 2008, and emergence of the influenza A(H1N1pdm09 virus in 2009. Oseltamivir is a prescription medicine in New Zealand, but more timely access has been provided since 2007 by allowing pharmacies to directly dispense oseltamivir to patients with influenza-like illness.Objective: To determine the frequency of oseltamivir-resistance in the context of a medicine reclassification in 2007, the importation of an oseltamivir-resistant seasonal influenza virus in 2008, and the emergence of a pandemic in 2009.Methods: A total of 1795 influenza viruses were tested for oseltamivir-resistance using a fluorometric neuraminidase inhibition assay. Viruses were collected as part of a sentinel influenza surveillance programme between the years 2006 and 2010.Results: All influenza B, influenza A(H3N2 and influenza A(H1N1pdm09 viruses tested between 2006 and 2010 were shown to be sensitive to oseltamivir. Seasonal influenza A(H1N1 viruses from 2008 and 2009 were resistant to oseltamivir. Sequencing of the neuraminidase gene showed that the resistant viruses contained an H275Y mutation, and S247N was also identified in the neuraminidase gene of one seasonal influenza A(H1N1 virus that exhibited enhanced resistance.Discussion: No evidence was found to suggest that increased access to oseltamivir has promoted resistance. A probable importation event was documented for the global 2008 oseltamivir-resistant seasonal A(H1N1 virus nine months after it was first reported in Europe in January 2008.

  2. Antiviral chemotherapy in veterinary medicine: current applications and perspectives.

    Science.gov (United States)

    Dal Pozzo, F; Thiry, E

    2014-12-01

    The current situation in the use of antiviral drugs in veterinary medicine is characterised by a novel and optimistic approach.Viruses of veterinary importance are still used as animal models in the developmentof human therapeutics, but there is growing interest in many of these viruses in the identification of antiviral molecules for use in both livestock and companion animals. The use of antiviral drugs in livestock animals is envisaged for the treatment or control of disease on a large scale (mass treatment), whereas in companion animals an individual approach is favoured. An overview of the most recent examples of research in the use of antivirals in veterinary medicine is presented, with particular emphasis on their in vivo applications.

  3. Oseltamivir (Tamiflu-induced bilateral acute angle closure glaucoma and transient myopia

    Directory of Open Access Journals (Sweden)

    Ji Woong Lee

    2014-01-01

    Full Text Available A 27-year-old woman developed bilateral acute angle closure glaucoma (AACG and transient myopia after taking oseltamivir for four days. On the fourth day, she received systemic and topical intraocular pressure (IOP-lowering agents, and IOP decreased in both eyes. However, her visual acuity was unchanged. A myopic shift of -5.25 D OD and -5.0 D OS was estimated to have occurred in the acute phase. A-scan ultrasonography and Pentacam showed markedly shallow anterior chambers and increased lens thickness. Ultrasound biomicroscopy revealed an annular ciliochoroidal effusion with forward displacement of the lens-iris diaphragm. Ciliochoroidal effusion and transient myopia were resolved after discontinuation of oseltamivir.

  4. Application of Heterogeneous Catalysts in the First Steps of the Oseltamivir Synthesis

    Directory of Open Access Journals (Sweden)

    José M. Fraile

    2017-12-01

    Full Text Available The first steps of oseltamivir synthesis from quinic acid involve acetalization and ester formation. These reactions are catalyzed by either acids or bases, which may be accomplished by heterogeneous catalysts. Sulfonic solids are efficient acid catalysts for acetalization and esterification reactions. Supported tetraalkylammonium hydroxide or 1,5,7-triazabicyclo[4.4.0]dec-5-ene are also efficient base catalysts for lactone alcoholysis and in this work, these catalysts have been applied in two alternative synthetic routes that lead to oseltamivir. The classical route consists of an acetalization, followed by a lactonization, and then a lactone alcoholysis. This achieves a 66% isolated yield. The alternative route consists of esterification followed by acetalization and is only efficient when an acetone acetal is used.

  5. Recent advances in the development of antiviral agents using computer-aided structure based approaches.

    Science.gov (United States)

    Kumar, Vikash; Chandra, Sharat; Siddiqi, Mohammad Imran

    2014-01-01

    Viral diseases have been affecting the human race since ancient times. Currently, a long list of diseases caused by the viruses is available and extensive research in this area has resulted in understanding the finest details of the molecular mechanism of pathogenesis caused by these pathogens. Side by side, efforts have been made towards the search and design of antiviral agents that could interfere with viral pathogenesis. As a result of these efforts a number of effective antiviral agents have been developed and are available in the market. However, the high cost and lengthy protocol of the drug discovery process are some of the major limiting factors in the development of new and more effective antiviral agents. Considering the above fact, presently the research community is trying to integrate short and cost effective techniques in the modern drug discovery process for the identification and design of novel antiviral agents. Computeraided drug design (CADD), which comprises of various techniques like molecular docking, virtual screening, three dimensional quantitative structure activity relationship (3D-QSAR) studies and many more, has the capability to speed up the antiviral drug development process. Successful design of antiviral drugs like Relenza, Saquinavir and Tamiflu have validated application of these techniques and holds a bright future in drug discovery protocol. This review explores the role of CADD in antiviral drug development and highlights the recent advances in antiviral drug research using computer-aided structure based approaches.

  6. A new ion selective electrode method for determination of oseltamivir phosphate (Tamiflu and its pharmaceutical applications

    Directory of Open Access Journals (Sweden)

    Salem M. Hamza

    2017-02-01

    The construction and electrochemical response characteristics of poly vinyl chloride (PVC membrane sensors for the determination of (OP were described. The sensors are based on the use of the ion association complexes of (OP cation with sodium tetraphenylborate–oseltamivir phosphate (NaTPB–OP, tungestosilisate–oseltamivir phosphate (TS–OP, phosphomolbdate–oseltamivir phosphate (PM–OP and phosphotungestate–oseltamivir phosphate (PT–OP as ion exchange sites in the PVC matrix. The performance characteristics of these sensors, which were evaluated according to IUPAC recommendations, reveal a fast, stable and linear response for (OP over the concentration range from 10−5 to 10−2 mol L−1 with cationic slopes of 51.5 ± 0.3, 50 ± 0.5, 55 ± 0.2 and 50 ± 0.4 mV per decade across an extended OP concentration range from 1.0 × 10−6 to 1.0 × 10−2 mol L−1 for NaTPB–OP, TS–OP, PM–OP and PT–OP, respectively. The direct potentiometric determination of (OP using the proposed sensors gave average recoveries of 99.9, 99.8, 99.9 and 99.7 for NaTPB–OP, TS–OP, PM–OP and PT–OP, respectively. The sensors are used for determination of (OP in tablets. The method was successfully applied to commercial pharmaceuticals, Tamiflu. Validation of the method shows suitability of the proposed sensors for use in the quality control assessment of (OP. The developed method was found to be simple, accurate and precise when compared with a reported HPLC method.

  7. Antiviral immunity in marine molluscs.

    Science.gov (United States)

    Green, Timothy J; Raftos, David; Speck, Peter; Montagnani, Caroline

    2015-09-01

    Marine molluscs, like all living organisms, are constantly exposed to viruses and have evolved efficient antiviral defences. We review here recent developments in molluscan antiviral immunity against viruses belonging to the order Herpesvirales. Emerging results suggest an interferon-like response and autophagy are involved in the antiviral defence of bivalves to viral infection. Multi-functional plasma proteins from gastropods and bivalves have been identified to have broad-spectrum antiviral activity against mammalian viruses. The antiviral defences present in molluscs can be enhanced by genetic selection, as shown by the presence of oyster strains specifically resistant to ostreid herpesvirus type 1. Whether varying amounts or different isoforms of these antiviral plasma proteins contributes to genetic resistance is worthy of further research. Other evolutionarily conserved antiviral mechanisms, such as RNA interference and apoptosis, still need further characterization.

  8. From genome to antivirals: SARS as a test tube.

    Science.gov (United States)

    Kliger, Yossef; Levanon, Erez Y; Gerber, Doron

    2005-03-01

    The severe acute respiratory syndrome (SARS) epidemic brought into the spotlight the need for rapid development of effective anti-viral drugs against newly emerging viruses. Researchers have leveraged the 20-year battle against AIDS into a variety of possible treatments for SARS. Most prominently, based solely on viral genome information, silencers of viral genes, viral-enzyme blockers and viral-entry inhibitors were suggested as potential therapeutic agents for SARS. In particular, inhibitors of viral entry, comprising therapeutic peptides, were based on the recently launched anti-HIV drug enfuvirtide. This could represent one of the most direct routes from genome sequencing to the discovery of antiviral drugs.

  9. Influenza A(H1N1)pdm09 virus exhibiting enhanced cross-resistance to oseltamivir and peramivir due to a dual H275Y/G147R substitution, Japan, March 2016.

    Science.gov (United States)

    Takashita, Emi; Fujisaki, Seiichiro; Shirakura, Masayuki; Nakamura, Kazuya; Kishida, Noriko; Kuwahara, Tomoko; Shimazu, Yukie; Shimomura, Takeshi; Watanabe, Shinji; Odagiri, Takato

    2016-06-16

    An influenza A(H1N1)pdm09 virus carrying a G147R substitution in combination with an H275Y substitution in the neuraminidase protein, which confers cross-resistance to oseltamivir and peramivir, was detected from an immunocompromised inpatient in Japan, March 2016. This dual H275Y/G147R mutant virus exhibited enhanced cross-resistance to both drugs compared with the single H275Y mutant virus and reduced susceptibility to zanamivir, although it showed normal inhibition by laninamivir. This article is copyright of The Authors, 2016.

  10. The Antiviral Activity of Approved and Novel Drugs against HIV-1 Mutations Evaluated under the Consideration of Dose-Response Curve Slope.

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    Shuai Chang

    Full Text Available This study was designed to identify common HIV-1 mutation complexes affecting the slope of inhibition curve, and to propose a new parameter incorporating both the IC50 and the slope to evaluate phenotypic resistance.Utilizing site-directed mutagenesis, we constructed 22 HIV-1 common mutation complexes. IC50 and slope of 10 representative approved drugs and a novel agent against these mutations were measured to determine the resistance phenotypes. The values of new parameter incorporating both the IC50 and the slope of the inhibition curve were calculated, and the correlations between parameters were assessed.Depending on the class of drug, there were intrinsic differences in how the resistance mutations affected the drug parameters. All of the mutations resulted in large increases in the IC50s of nucleoside reverse transcriptase inhibitors. The effects of the mutations on the slope were the most apparent when examining their effects on the inhibition of non-nucleoside reverse transcriptase inhibitors and protease inhibitors. For example, some mutations, such as V82A, had no effect on IC50, but reduced the slope. We proposed a new concept, termed IIPatoxic, on the basis of IC50, slope and the maximum limiting concentrations of the drug. The IIPatoxic values of 10 approved drugs and 1 novel agent were calculated, and were closely related to the IIPmax values (r > 0.95, p < 0.001.This study confirms that resistance mutations cannot be accurately assessed by IC50 alone, because it tends to underestimate the degree of resistance. The slope parameter is of very importance in the measurement of drug resistance and the effect can be applied to more complex patterns of resistance. This is the most apparent when testing the effects of the mutations on protease inhibitors activity. We also propose a new index, IIPatoxic, which incorporates both the IC50 and the slope. This new index could complement current IIP indices, thereby enabling predict the

  11. [Studies on evaluation of natural products for antiviral effects and their applications].

    Science.gov (United States)

    Hayashi, Toshimitsu

    2008-01-01

    In the search for novel antiviral molecules from natural products, we have discovered various antiviral molecules with characteristic mechanisms of action. Scopadulciol (SDC), isolated from the tropical medicinal plant Scoparia dulcis L., showed stimulatory effects on the antiviral potency of acyclovir (ACV) or ganciclovir (GCV). This effect of SDC was exerted via the activation of viral thymidine kinase (HSV-1 TK) and, as a result, an increase in the cellular concentration of the active form of ACV/GCV, i.e., the triphosphate of ACV or GCV. On the basis of these experimental results, cancer gene therapy using the HSV-1 tk gene and ACV/GCV together with SDC was found to be effective in suppressing the growth of cancer cells in animals. Acidic polysaccharides such as calcium spirulan (Ca-SP) from Spirulina platensis, nostoflan from Nostoc flagelliforme, and a fucoidan from the sporophyll of Undaria pinnatifida (mekabu fucoidan) were also found to be potent inhibitors against several enveloped viruses. Their antiviral potency was dependent on molecular weight and content of the sulfate or carboxyl group as well as counterion species chelating with sulfate groups, indicating the importance of the three-dimensional structure of the molecules. In addition, unlike dextran sulfate, Ca-SP was shown to target not only viral absorption/penetration stages but also some replication stages of progeny viruses after penetration into cells. When mekabu fucoidan or nostoflan was administered with oseltamivir phosphate, their synergistic antiviral effects on influenza A virus were confirmed in vitro as well as in vivo.

  12. [Antiviral properties of basidiomycetes metabolites].

    Science.gov (United States)

    Avtonomova, A V; Krasnopolskaya, L M

    2014-01-01

    The data on the antiviral action of the Ganoderma lucidum, Lentinus edodes, Grifola frondosa, Agaricus brasiliensis and other basidiomycetes metabolites are summurized. The metabolites of these species of basidiomycetes exhibit a direct antiviral effect on herpes simplex virus types I and II, human immunodeficiency virus (HIV), hepatitis B virus, vesicular stomatitis virus, influenza virus, Epstein-Barr virus, and others. Moreover, metabolites of basidiomycetes increased antiviral immunity.

  13. Mitochondria and antiviral innate immunity

    OpenAIRE

    Koshiba, Takumi; Bashiruddin, Nasir; Kawabata, Shunichiro

    2011-01-01

    Mitochondria, dynamic organelles that undergo continuous cycles of fusion and fission, are the powerhouses of eukaryotic cells. Recent research indicates that mitochondria also act as platforms for antiviral immunity in vertebrates. Mitochondrial-mediated antiviral immunity depends on activation of the retinoic acid-inducible gene I (RIG-I)-like receptors signal transduction pathway and the participation of the mitochondrial outer membrane adaptor protein “mitochondrial antiviral signaling (M...

  14. CRM1 Inhibitors for Antiviral Therapy

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    Cynthia Mathew

    2017-06-01

    Full Text Available Infectious diseases are a major global concern and despite major advancements in medical research, still cause significant morbidity and mortality. Progress in antiviral therapy is particularly hindered by appearance of mutants capable of overcoming the effects of drugs targeting viral components. Alternatively, development of drugs targeting host proteins essential for completion of viral lifecycle holds potential as a viable strategy for antiviral therapy. Nucleocytoplasmic trafficking pathways in particular are involved in several pathological conditions including cancer and viral infections, where hijacking or alteration of function of key transporter proteins, such as Chromosome Region Maintenance1 (CRM1 is observed. Overexpression of CRM1-mediated nuclear export is evident in several solid and hematological malignancies. Interestingly, CRM1-mediated nuclear export of viral components is crucial in various stages of the viral lifecycle and assembly. This review summarizes the role of CRM1 in cancer and selected viruses. Leptomycin B (LMB is the prototypical inhibitor of CRM1 potent against various cancer cell lines overexpressing CRM1 and in limiting viral infections at nanomolar concentrations in vitro. However, the irreversible shutdown of nuclear export results in high cytotoxicity and limited efficacy in vivo. This has prompted search for synthetic and natural CRM1 inhibitors that can potentially be developed as broadly active antivirals, some of which are summarized in this review.

  15. Perspective of Use of Antiviral Peptides against Influenza Virus

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    Sylvie Skalickova

    2015-10-01

    Full Text Available The threat of a worldwide influenza pandemic has greatly increased over the past decade with the emergence of highly virulent avian influenza strains. The increased frequency of drug-resistant influenza strains against currently available antiviral drugs requires urgent development of new strategies for antiviral therapy, too. The research in the field of therapeutic peptides began to develop extensively in the second half of the 20th century. Since then, the mechanisms of action for several peptides and their antiviral prospect received large attention due to the global threat posed by viruses. Here, we discussed the therapeutic properties of peptides used in influenza treatment. Peptides with antiviral activity against influenza can be divided into three main groups. First, entry blocker peptides such as a Flupep that interact with influenza hemagglutinin, block its binding to host cells and prevent viral fusion. Second, several peptides display virucidal activity, disrupting viral envelopes, e.g., Melittin. Finally, a third set of peptides interacts with the viral polymerase complex and act as viral replication inhibitors such as PB1 derived peptides. Here, we present a review of the current literature describing the antiviral activity, mechanism and future therapeutic potential of these influenza antiviral peptides.

  16. Cost effectiveness of oseltamivir treatment for patients with influenza-like illness who are at increased risk for serious complications of influenza - Illustration for the Netherlands

    NARCIS (Netherlands)

    Postma, Maarten J.; Novak, Annoesjka; Scheijbeler, Huib W. K. F. H.; Gyldmark, Marlene; van Genugten, Marianne L. L.; Wilschut, Jan C.

    2007-01-01

    Background: Oseltamivir is effective in the treatment of influenza. Utilisation in The Netherlands is limited, but increasing. Objective: To estimate the cost effectiveness of oseltamivir treatment (vs symptom relief only) for patients with influenza-like illness (ILI) who are at increased risk for

  17. Broad-spectrum antiviral properties of andrographolide.

    Science.gov (United States)

    Gupta, Swati; Mishra, K P; Ganju, Lilly

    2017-03-01

    Andrographolide, a diterpenoid, is known for its anti-inflammatory effects. It can be isolated from various plants of the genus Andrographis, commonly known as 'creat'. This purified compound has been tested for its anti-inflammatory effects in various stressful conditions, such as ischemia, pyrogenesis, arthritis, hepatic or neural toxicity, carcinoma, and oxidative stress, Apart from its anti-inflammatory effects, andrographolide also exhibits immunomodulatory effects by effectively enhancing cytotoxic T cells, natural killer (NK) cells, phagocytosis, and antibody-dependent cell-mediated cytotoxicity (ADCC). All these properties of andrographolide form the foundation for the use of this miraculous compound to restrain virus replication and virus-induced pathogenesis. The present article covers antiviral properties of andrographolide in variety of viral infections, with the hope of developing of a new highly potent antiviral drug with multiple effects.

  18. Combined Analysis of the Prevalence of Drug-Resistant Hepatitis B Virus in Antiviral Therapy-Experienced Patients in Europe (CAPRE)

    DEFF Research Database (Denmark)

    Hermans, Lucas Etienne; Svicher, Valentina; Pas, Suzan Diepstraten

    2016-01-01

    was performed to gain insight in prevalence and characteristics of NA resistance in Europe. METHODS: A survey was performed on genotypic resistance testing results acquired during routine monitoring of CHB patients with detectable serum hepatitis B virus DNA in European tertiary referral centers. RESULTS: Data...... from 1568 patients were included. The majority (73.8%) were exposed to lamivudine monotherapy. Drug-resistant strains were detected in 52.7%. The most frequently encountered primary mutation was M204V/I (48.7%), followed by A181T/V (3.8%) and N236T (2.6%). In patients exposed to entecavir (n = 102...

  19. Understanding real-world adherence in the directly acting antiviral era: A prospective evaluation of adherence among people with a history of drug use at a community-based program in Toronto, Canada.

    Science.gov (United States)

    Mason, Kate; Dodd, Zoë; Guyton, Mary; Tookey, Paula; Lettner, Bernadette; Matelski, John; Sockalingam, Sanjeev; Altenberg, Jason; Powis, Jeff

    2017-09-01

    Direct acting antiviral (DAA) treatments for Hepatitis C (HCV) are now widely available with sustained virologic response (SVR) rates of >90%. A major predictor of response to DAAs is adherence, yet few real-world studies evaluating adherence among marginalized people who use drugs and/or alcohol exist. This study evaluates patterns and factors associated with non-adherence among marginalized people with a history of drug use who were receiving care through a primary care, community-based HCV treatment program where opiate substitution is not offered on-site. Prospective evaluation of chronic HCV patients initiating DAA treatment. Self-report medication adherence questionnaires were completed weekly. Pre/post treatment questionnaires examined socio-demographics, program engagement and substance use. Missing adherence data was counted as a missed dose. Of the 74 participants, who initiated treatment, 76% were male, the average age was 54 years, 69% reported income from disability benefits, 30% did not have stable housing and only 24% received opiate substitution therapy. Substance use was common in the month prior to treatment initiation with, 11% reported injection drug use, 30% reported non-injection drug use and 18% moderate to heavy alcohol use. The majority (85%) were treatment naïve, with 76% receiving sofosbuvir/ledipasvir (8-24 weeks) and 22% Sofosbuvir/Ribarvin (12-24 weeks). The intention to treat proportion with SVR12 was 87% (60/69). In a modified ITT analysis (excluding those with undetectable RNA at end of treatment), 91% (60/66) achieved SVR12. Overall, 89% of treatment weeks had no missed doses. 41% of participants had at least one missed dose. In multivariate analysis the only factor independently associated with weeks with missed doses was moderate to heavy alcohol use (p=0.05). This study demonstrates that strong adherence and SVR with DAAs is achievable, with appropriate supports, even in the context of substance use, and complex health

  20. WITHDRAWN. Antiviral treatment for Bell's palsy (idiopathic facial paralysis).

    Science.gov (United States)

    Gagyor, Ildiko; Madhok, Vishnu B; Daly, Fergus; Somasundara, Dhruvashree; Sullivan, Michael; Gammie, Fiona; Sullivan, Frank

    2015-05-04

    Corticosteroids are widely used in the treatment of idiopathic facial paralysis (Bell's palsy), but the effectiveness of additional treatment with an antiviral agent is uncertain. Significant morbidity can be associated with severe cases of Bell's palsy. To assess the effects of antiviral treatments alone or in combination with any other therapy for Bell's palsy. On 7 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, DARE, NHS EED, and HTA. We also reviewed the bibliographies of the identified trials and contacted trial authors and known experts in the field and relevant drug companies to identify additional published or unpublished data. We searched clinical trials registries for ongoing studies. We considered randomised controlled trials or quasi-randomised controlled trials of antivirals with and without corticosteroids versus control therapies for the treatment of Bell's palsy. We excluded trials that had a high risk of bias in several domains. Pairs of authors independently assessed trials for relevance, eligibility, and risk of bias, using standard Cochrane procedures. Eleven trials, including 2883 participants, met the inclusion criteria and are included in the final analysis. We added four studies to the previous review for this update. Some of the trials were small, and a number were at high or unclear risk of bias. Other trials did not meet current best standards in allocation concealment and blinding. Incomplete recoveryWe found no significant benefit from adding antivirals to corticosteroids in comparison with corticosteroids alone for people with Bell's palsy (risk ratio (RR) 0.69, 95% confidence interval (CI) 0.47 to 1.02, n = 1715). For people with severe Bell's palsy (House-Brackmann scores of 5 and 6 or the equivalent in other scales), we found a reduction in the rate of incomplete recovery at month six when antivirals plus corticosteroids were used (RR 0.64, 95% CI 0.41 to 0

  1. Clinical course of asthma patients with H1N1 influenza infection and oseltamivir.

    Science.gov (United States)

    Kim, Min-Hye; Song, Woo-Jung; Yang, Min-Suk; Lee, So-Hee; Kwon, Jae-Woo; Kim, Sae-Hoon; Kang, Hye-Ryun; Park, Heung-Woo; Cho, Young-Joo; Cho, Sang-Heon; Min, Kyung-Up; Kim, You-Young; Chang, Yoon-Seok

    2018-02-01

    H1N1 influenza virus prevailed throughout the world in 2009. However, there are few reports on the clinical features of H1N1 influenza infection in adult asthma patients. We evaluated the clinical features in asthma patients with H1N1 influenza infection who took oseltamivir and compared them to those with other upper respiratory infections. We reviewed asthma patients over 15 years of age who had visited Seoul National University Hospital and Seoul National University Bundang Hospital for suspected H1N1 influenza infection from August 2009 to March 2010. Various clinical features such as hospital admission days, respiratory symptoms, basal lung function, and past history was compared between H1N1 influenza PCR positive and negative groups. A total of 111 asthmatics were enrolled. All patients took oseltamivir. H1N1 RT-PCR was positive in 62 patients (55.9%), negative in 49 patients (44.1%). Wheezing developed more frequently in the H1N1 positive group. (43.5 vs. 16.7%, P=0.044). The rate of acute asthma exacerbations and pneumonia development were higher in the H1N1 positive group (59.7 vs. 51%, P=0.015, 25.0% vs. 0%, PH1N1 negative patients (21.6% vs. 30.6%, P=0.002), especially cardiac disease (7.2% vs. 15.3%, P=0.011). H1N1 influenza infection may affect the clinical course of asthma combined with more severe manifestations; however, Oseltamivir could have affected the clinical course of H1N1 infected patients and made it milder than expected.

  2. La respuesta inmune antiviral

    Directory of Open Access Journals (Sweden)

    Rainel Sánchez de la Rosa

    1998-02-01

    Full Text Available Se expone que los virus son parásitos intracelulares obligados, puesto que no tienen metabolismo propio; esto obliga al sistema inmune a poner en marcha sus mecanismos más especializados para reconocer y eliminar, tanto a los virus libres, como a las células infectadas. Se señala que las células presentadoras de antígenos, los linfocitos B y los T unidos al complejo mayor de histocompatibilidad, forman parte de la organización de la respuesta inmune antiviral; la inducción de esta respuesta con proteínas, péptidos y ADN desnudo, son alternativas actuales tanto en la prevención como en el tratamiento de las infecciones viralesIt is explained that viruses are compulsory intracellular parasites, since they don't have their own metabolism, which makes the immune system to start its mest specialized mechanisms to recognize and eliminate the free viruses and the infected cells. It is stated that the cells presenting antigens, and the B and T lymphocytes together with the major histocompatibility complex, are part of the organization of the immune antiviral response. The induction of this response with proteins, peptides and naked DNA are the present alternatives for the prevention and treatment of viral infections

  3. ANTI-VIRAL ACTIVITY OF GLYCIRRHETINIC AND GLYCIRRHIZIC ACIDS

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    V. V. Zarubaev

    2016-01-01

    Full Text Available Influenza is a highly contagious human disease. In the course of use of antiviral drugs drug-resistant strains of the virus are formed, resulting in reduced efficiency of the chemotherapy. The review describes the biological activity of glycirrhetinic (GLA and glycirrhizic (GA acids in terms of their use as a therapeutic agent for viral infections. So, these compounds are against a broad spectrum of viruses, including herpes, corona-, alphaand flaviviruses, human immunodeficiency virus, vaccinia virus, poliovirus type I, vesicular stomatitis virus and influenza A virus. These data indicate that anti-viral effect of these compounds is due to several types of activity — direct antiviral effects, effects on cellular proand anti-viral and immunomodulating pathways, in particular by activation of innate immunity system. GA interferes with early steps of the viral reproductive cycle such as virus binding to its receptor, the absorption of the virus by endocytosis or virus decapsidation in the cytoplasm. This is due to the effect of GA-induced reduction of membrane fluidity. Thus, one mechanism for the antiviral activity of GA is that GA molecule increases the rigidity of cellular and viral membranes after incorporation in there. This results in increasing of energy threshold required for the formation of negative curvature at the fusion zones, as well as difficult lateral migration of the virus-receptor complexes. In addition, glycyrrhizin prevents interaction of viral nucleoprotein with cellular protein HMGB1, which is necessary for the viral life cycle. Glycyrrhizin also inhibits the induction of oxidative stress during influenza infection, exhibiting antioxidant properties, which leads to a reduction of virus-induced production of cytokines/chemokines, without affecting the replication of the virus. A wide spectrum of biological activity and effect on various aspects of the viral pathogenesis substantiate the effect of GA and GLA as a component

  4. The Potential Impact of a Hepatitis C Vaccine for People Who Inject Drugs: Is a Vaccine Needed in the Age of Direct-Acting Antivirals?

    Directory of Open Access Journals (Sweden)

    Jack Stone

    Full Text Available The advent of highly effective hepatitis C (HCV treatments has questioned the need for a vaccine to control HCV amongst people who inject drugs (PWID. However, high treatment costs and ongoing reinfection risk suggest it could still play a role. We compared the impact of HCV vaccination amongst PWID against providing HCV treatment.Dynamic HCV vaccination and treatment models among PWID were used to determine the vaccination and treatment rates required to reduce chronic HCV prevalence or incidence in the UK over 20 or 40 years. Projections considered a low (50% protection for 5 years, moderate (70% protection for 10 years or high (90% protection for 20 years efficacy vaccine. Sensitivities to various parameters were examined.To halve chronic HCV prevalence over 40 years, the low, moderate and high efficacy vaccines required annual vaccination rates (coverage after 20 years of 162 (72%, 77 (56% and 44 (38% per 1000 PWID, respectively. These vaccination rates were 16, 7.6 and 4.4 times greater than corresponding treatment rates. To halve prevalence over 20 years nearly doubled these vaccination rates (moderate and high efficacy vaccines only and the vaccination-to-treatment ratio increased by 20%. For all scenarios considered, required annual vaccination rates and vaccination-to-treatment ratios were at least a third lower to reduce incidence than prevalence. Baseline HCV prevalence had little effect on the vaccine's impact on prevalence or incidence, but substantially affected the vaccination-to-treatment ratios. Behavioural risk heterogeneity only had an effect if we assumed no transitions between high and low risk states and vaccinations were targeted or if PWID were high risk for their first year.Achievable coverage levels of a low efficacy prophylactic HCV vaccine could greatly reduce HCV transmission amongst PWID. Current high treatment costs ensure vaccination could still be an important intervention option.

  5. Autodisplay of an archaeal γ-lactamase on the cell surface of Escherichia coli using Xcc_Est as an anchoring scaffold and its application for preparation of the enantiopure antiviral drug intermediate (-) vince lactam.

    Science.gov (United States)

    Wang, Jianjun; Zhao, Guogang; Zhang, Zhiwei; Liang, Qiulin; Min, Cong; Wu, Sheng

    2014-08-01

    At present, autotransporter protein mediated surface display has opened a new dimension in the development of whole-cell biocatalysts. Here, we report the identification of a novel autotransporter Xcc_Est from Xanthomonas campestris pv campestris 8004 by bioinformatic analysis and application of Xcc_Est as an anchoring motif for surface display of γ-lactamase (Gla) from thermophilic archaeon Sulfolobus solfataricus P2 in Escherichia coli. The localization of γ-lactamase in the cell envelope was monitored by Western blot, activity assay and flow cytometry analysis. Either the full-length or truncated Xcc_Est could efficiently transport γ-lactamase to the cell surface. Compared with the free enzyme, the displayed γ-lactamase exhibited optimum temperature of 30 °C other than 90 °C, with a substantial decrease of 60 °C. Under the preparation system, the engineered E. coli with autodisplayed γ-lactamase converted 100 g racemic vince lactam to produce 49.2 g (-) vince lactam at 30 °C within 4 h. By using chiral HPLC, the ee value of the produced (-) vince lactam was determined to be 99.5 %. The whole-cell biocatalyst exhibited excellent stability under the operational conditions. Our results indicate that the E. coli with surface displayed γ-lactamase is an efficient and economical whole cell biocatalyst for preparing the antiviral drug intermediate (-) vince lactam at mild temperature, eliminating expensive energy cost performed at high temperature.

  6. Atividade de três drogas antivirais sobre os herpesvírus bovino tipos 1, 2 e 5 em cultivo celular Activity of three antiviral drugs against bovine herpesviruses 1, 2 and 5 in cell culture

    Directory of Open Access Journals (Sweden)

    Renata Dezengrini

    2010-10-01

    Full Text Available A atividade de três fármacos antivirais (Aciclovir [ACV], Ganciclovir [GCV] e Foscarnet [PFA] foi testada in vitro frente aos herpesvírus bovino tipos 1 (BoHV-1, 2 (BoHV-2 e 5 (BoHV-5. Para isso, utilizou-se o teste de reducao de placas virais em cultivo celular, testando-se diferentes concentracoes dos farmacos frente a 100 doses infectantes para 50% dos cultivos celulares (DICC50 dos respectivos virus. Pelo teste de MTT (3-(4,5-Dimethylthiazol- 2-yl-2,5-diphenyltetrazolium bromide, verificou-se que concentracoes inferiores a 200ƒÊg/mL dos tres antivirais resultaram em indices de viabilidade de celulas MDBK e Hep2 superiores a 80%. Com base na concentracao citotoxica para 50% das celulas (CC50 e na concentracao dos farmacos efetiva para inibir em 50% o numero de placas virais (EC50, calculou-se o indice de seletividade (IS dos antivirais para os tres herpesvirus. Assim, o ACV demonstrou ser moderadamente ativo frente ao BoHV-1 (EC50: 112,9ƒÊg/mL e IS: 4,5, ao BoHV-2 (EC50: 114,2 ƒÊg/mL e IS: 4,5 e BoHV-5 (EC50: 96,9ƒÊg/mL e IS: 5,3. O GCV apresentou atividade moderada frente ao BoHV-2 (EC50: 33,5ƒÊg/mL e IS: 16,6 e, em menor grau, contra o BoHV-5 (EC50: 123,2ƒÊg/mL e IS: 4,5, sendo ineficaz frente ao BoHV-1 (EC50: 335,8ƒÊg/mL e IS: 1,7. O PFA apresentou atividade antiviral mais pronunciada, sendo o unico farmaco que, na concentracao de 100ƒÊg/mL, inibiu completamente a producao de placas pelos tres virus testados. O PFA foi o mais efetivo in vitro frente ao BoHV-1 (EC50: 29,5ƒÊg/mL e IS: 42,2, ao BoHV-2 (EC50: 45,2ƒÊg/mL e IS: 27,6 e ao BoHV-5 (EC50: 7,8ƒÊg/mL e IS: 160,6. Portanto, os resultados obtidos indicam que o PFA pode se constituir em um candidato para terapia experimental de infeccoes pelos herpesvirus de bovinos in vivo.The activity of three anti-herpetic drugs (Acyclovir [ACV], Gancyclovir [GCV] and Foscarnet [PFA] was tested against bovine herpesvirus 1 (BoHV-1, 2 (BoHV-2 and 5 (BoHV-5 in vitro using the

  7. Antiviral immunity in amphibians.

    Science.gov (United States)

    Chen, Guangchun; Robert, Jacques

    2011-11-01

    Although a variety of virus species can infect amphibians, diseases caused by ranaviruses ([RVs]; Iridoviridae) have become prominent, and are a major concern for biodiversity, agriculture and international trade. The relatively recent and rapid increase in prevalence of RV infections, the wide range of host species infected by RVs, the variability in host resistance among population of the same species and among different developmental stages, all suggest an important involvement of the amphibian immune system. Nevertheless, the roles of the immune system in the etiology of viral diseases in amphibians are still poorly investigated. We review here the current knowledge of antiviral immunity in amphibians, focusing on model species such as the frog Xenopus and the salamander (Ambystoma tigrinum), and on recent progress in generating tools to better understand how host immune defenses control RV infections, pathogenicity, and transmission.

  8. Aciclovir: nuevo antiviral

    Directory of Open Access Journals (Sweden)

    G. Repetto

    2017-05-01

    Full Text Available El aciclovir es un antiviral útil en infecciones graves causadas por el virus varicela-zoster. Es bien tolerado con escasas reacciones adversas. En pacientes deshidratados, en insuficiencia renal o si la infusión endovenosa es muy rápida, puede ocacionar una "nefropatía obstructiva" transitoria. Existen preparados de uso tópico, oftálmico, endovenoso y oral; esta última vía constituye una ventaja sobre la vidarabina con la que tiene en común el espectro de actividad. En razón de su selectividad, riesgo de resistencia y número reducido de antivirales, su prescripción debe restringirse a infecciones graves causadas por los agentes inmunodeprimidos; excluyendo por lo tanto las comunes y autolimitadas, frecuentes en el individuo normal.

  9. Screening for Antiviral Activities of Isolated Compounds from Essential Oils

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    Akram Astani

    2011-01-01

    Full Text Available Essential oil of star anise as well as phenylpropanoids and sesquiterpenes, for example, trans-anethole, eugenol, β-eudesmol, farnesol, β-caryophyllene and β-caryophyllene oxide, which are present in many essential oils, were examined for their antiviral activity against herpes simplex virus type 1 (HSV-1 in vitro. Antiviral activity was analyzed by plaque reduction assays and mode of antiviral action was determined by addition of the drugs to uninfected cells, to the virus prior to infection or to herpesvirus-infected cells. Star anise oil reduced viral infectivity by >99%, phenylpropanoids inhibited HSV infectivity by about 60–80% and sesquiterpenes suppressed herpes virus infection by 40–98%. Both, star anise essential oil and all isolated compounds exhibited anti-HSV-1 activity by direct inactivation of free virus particles in viral suspension assays. All tested drugs interacted in a dose-dependent manner with herpesvirus particles, thereby inactivating viral infectivity. Star anise oil, rich in trans-anethole, revealed a high selectivity index of 160 against HSV, whereas among the isolated compounds only β-caryophyllene displayed a high selectivity index of 140. The presence of β-caryophyllene in many essential oils might contribute strongly to their antiviral ability. These results indicate that phenylpropanoids and sesquiterpenes present in essential oils contribute to their antiviral activity against HSV.

  10. Cytomegalovirus Antivirals and Development of Improved Animal Models

    Science.gov (United States)

    McGregor, Alistair; Choi, K. Yeon

    2015-01-01

    Introduction Cytomegalovirus (CMV) is a ubiquitous pathogen that establishes a life long asymptomatic infection in healthy individuals. Infection of immunesuppressed individuals causes serious illness. Transplant and AIDS patients are highly susceptible to CMV leading to life threatening end organ disease. Another vulnerable population is the developing fetus in utero, where congenital infection can result in surviving newborns with long term developmental problems. There is no vaccine licensed for CMV and current antivirals suffer from complications associated with prolonged treatment. These include drug toxicity and emergence of resistant strains. There is an obvious need for new antivirals. Candidate intervention strategies are tested in controlled pre-clinical animal models but species specificity of HCMV precludes the direct study of the virus in an animal model. Areas covered This review explores the current status of CMV antivirals and development of new drugs. This includes the use of animal models and the development of new improved models such as humanized animal CMV and bioluminescent imaging of virus in animals in real time. Expert Opinion Various new CMV antivirals are in development, some with greater spectrum of activity against other viruses. Although the greatest need is in the setting of transplant patients there remains an unmet need for a safe antiviral strategy against congenital CMV. This is especially important since an effective CMV vaccine remains an elusive goal. In this capacity greater emphasis should be placed on suitable pre-clinical animal models and greater collaboration between industry and academia. PMID:21883024

  11. Liposomal Systems as Nanocarriers for the Antiviral Agent Ivermectin

    Directory of Open Access Journals (Sweden)

    Romina Croci

    2016-01-01

    Full Text Available RNA virus infections can lead to the onset of severe diseases such as fever with haemorrhage, multiorgan failure, and mortality. The emergence and reemergence of RNA viruses continue to pose a significant public health threat worldwide with particular attention to the increasing incidence of flaviviruses, among others Dengue, West Nile Virus, and Yellow Fever viruses. Development of new and potent antivirals is thus urgently needed. Ivermectin, an already known antihelminthic drug, has shown potent effects in vitro on Flavivirus helicase, with EC50 values in the subnanomolar range for Yellow Fever and submicromolar EC50 for Dengue Fever, Japanese encephalitis, and tick-borne encephalitis viruses. However ivermectin is hampered in its application by pharmacokinetic problems (little solubility and high cytotoxicity. To overcome such problems we engineered different compositions of liposomes as ivermectin carriers characterizing and testing them on several cell lines for cytotoxicity. The engineered liposomes were less cytotoxic than ivermectin alone and they showed a significant increase of the antiviral activity in all the Dengue stains tested (1, 2, and S221. In the current study ivermectin is confirmed to be an effective potential antiviral and liposomes, as drug carriers, are shown to modulate the drug activity. All together the results represent a promising starting point for future improvement of ivermectin as antiviral and its delivery.

  12. Antiviral properties from plants of the Mediterranean flora.

    Science.gov (United States)

    Sanna, G; Farci, P; Busonera, B; Murgia, G; La Colla, P; Giliberti, G

    2015-01-01

    Natural products are a successful source in drug discovery, playing a significant role in maintaining human health. We investigated the in vitro cytotoxicity and antiviral activity of extracts from 18 traditionally used Mediterranean plants. Noteworthy antiviral activity was found in the extract obtained from the branches of Daphne gnidium L. against human immunodeficiency virus type-1 (EC50 = 0.08 μg/mL) and coxsackievirus B5 (EC50 = 0.10 μg/mL). Other relevant activities were found against BVDV, YFV, Sb-1, RSV and HSV-1. Interestingly, extracts from Artemisia arborescens L. and Rubus ulmifolius Schott, as well as those from D. gnidium L., showed activities against two different viruses. This extensive antiviral screening allowed us to identify attractive activities, offering opportunities to develop lead compounds with a great pharmaceutical potential.

  13. Antiviral treatment for Bell's palsy (idiopathic facial paralysis

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    Ildiko Gagyor

    Full Text Available ABSTRACTBACKGROUND: Corticosteroids are widely used in the treatment of idiopathic facial paralysis (Bell's palsy, but the effectiveness of additional treatment with an antiviral agent is uncertain. Significant morbidity can be associated with severe cases of Bell's palsy.OBJECTIVES: To assess the effects of antiviral treatments alone or in combination with any other therapy for Bell's palsy.METHODS:Search methods:On 7 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, DARE, NHS EED, and HTA. We also reviewed the bibliographies of the identified trials and contacted trial authors and known experts in the field and relevant drug companies to identify additional published or unpublished data. We searched clinical trials registries for ongoing studies.Selection criteria:We considered randomised controlled trials or quasi-randomised controlled trials of antivirals with and without corticosteroids versus control therapies for the treatment of Bell's palsy.We excluded trials that had a high risk of bias in several domains.Data collection and analysis:Pairs of authors independently assessed trials for relevance, eligibility, and risk of bias, using standard Cochrane procedures.MAIN RESULTS: Eleven trials, including 2883 participants, met the inclusion criteria and are included in the final analysis. We added four studies to the previous review for this update. Some of the trials were small, and a number were at high or unclear risk of bias. Other trials did not meet current best standards in allocation concealment and blinding. Incomplete recovery:We found no significant benefit from adding antivirals to corticosteroids in comparison with corticosteroids alone for people with Bell's palsy (risk ratio (RR 0.69, 95% confidence interval (CI 0.47 to 1.02, n = 1715. For people with severe Bell's palsy (House Brackmann scores of 5 and 6 or the equivalent in other scales, we found a

  14. Pharmacokinetic Modeling and Monte Carlo Simulation to Predict Interindividual Variability in Human Exposure to Oseltamivir and Its Active Metabolite, Ro 64-0802.

    Science.gov (United States)

    Ito, Mototsugu; Kusuhara, Hiroyuki; Ose, Atsushi; Kondo, Tsunenori; Tanabe, Kazunari; Nakayama, Hideki; Horita, Shigeru; Fujita, Takuya; Sugiyama, Yuichi

    2017-01-01

    Oseltamivir (Tamiflu®) is a prodrug of Ro 64-0802, a selective inhibitor of influenza virus neuraminidase. There is a possible relationship between oseltamivir treatment and neuropsychiatric adverse events; although this has not been established, close monitoring is recommended on the prescription label. The objective of this study was to predict interindividual variability of human exposure to oseltamivir and its active metabolite Ro 64-0802. By leveraging mathematical models and computations, physiological parameters in virtual subjects were generated with population means and coefficient of variations collected from the literature or produced experimentally. Postulated functional changes caused by genetic mutations in four key molecules, carboxylesterase 1A1, P-glycoprotein, organic anion transporter 3, and multidrug resistance-associated protein 4, were also taken into account. One hundred thousand virtual subjects were generated per simulation, which was iterated 20 times with different random number generator seeds. Even in the most exaggerated case, the systemic areas under the concentration-time curve (AUCs) of oseltamivir and Ro 64-0802 were increased by at most threefold compared with the population mean. By contrast, the brain AUCs of oseltamivir and Ro 64-0802 were increased up to about sevenfold and 40-fold, respectively, compared with the population means. This unexpectedly high exposure to oseltamivir or Ro 64-0802, which occurs extremely rarely, might trigger adverse central nervous system effects in the clinical setting.

  15. Assessment of the antiviral properties of recombinant surfactant protein D against influenza B virus in vitro.

    Science.gov (United States)

    Hillaire, Marine L B; van Eijk, Martin; Vogelzang-van Trierum, Stella E; Nieuwkoop, Nella J; van Riel, Debby; Fouchier, Ron A M; Kuiken, Thijs; Osterhaus, Albert D M E; Haagsman, Henk P; Rimmelzwaan, Guus F

    2015-01-02

    The armamentarium of antiviral drugs against influenza viruses is limited. Furthermore, influenza viruses emerge that are resistant to existing antiviral drugs like the M2 and NA inhibitors. Therefore, there is an urgent need for the development of novel classes of antiviral drugs. Here we investigated the antiviral properties of recombinant porcine surfactant protein D (RpSP-D), an innate defense molecule with lectin properties, against influenza B viruses. We have previously shown that porcine SP-D has more potent neutralizing activity against influenza A viruses than human SP-D. Here we show that RpSP-D neutralizes influenza B viruses efficiently and inhibited the binding of these viruses to epithelial cells of the human trachea. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Viral ancestors of antiviral systems.

    Science.gov (United States)

    Villarreal, Luis P

    2011-10-01

    All life must survive their corresponding viruses. Thus antiviral systems are essential in all living organisms. Remnants of virus derived information are also found in all life forms but have historically been considered mostly as junk DNA. However, such virus derived information can strongly affect host susceptibility to viruses. In this review, I evaluate the role viruses have had in the origin and evolution of host antiviral systems. From Archaea through bacteria and from simple to complex eukaryotes I trace the viral components that became essential elements of antiviral immunity. I conclude with a reexamination of the 'Big Bang' theory for the emergence of the adaptive immune system in vertebrates by horizontal transfer and note how viruses could have and did provide crucial and coordinated features.

  17. Viral Ancestors of Antiviral Systems

    Directory of Open Access Journals (Sweden)

    Luis P. Villarreal

    2011-10-01

    Full Text Available All life must survive their corresponding viruses. Thus antiviral systems are essential in all living organisms. Remnants of virus derived information are also found in all life forms but have historically been considered mostly as junk DNA. However, such virus derived information can strongly affect host susceptibility to viruses. In this review, I evaluate the role viruses have had in the origin and evolution of host antiviral systems. From Archaea through bacteria and from simple to complex eukaryotes I trace the viral components that became essential elements of antiviral immunity. I conclude with a reexamination of the ‘Big Bang’ theory for the emergence of the adaptive immune system in vertebrates by horizontal transfer and note how viruses could have and did provide crucial and coordinated features.

  18. Spectroscopic investigation of herpes simplex viruses infected cells and their response to antiviral therapy

    Science.gov (United States)

    Erukhimovitch, Vitaly; Talyshinsky, Marina; Souprun, Yelena; Huleihel, Mahmoud

    2006-07-01

    In the present study, we used microscopic Fourier transform infrared spectroscopy (FTIR) to evaluate the antiviral activity of known antiviral agents against herpes viruses. The antiviral activity of Caffeic acid phenethyl ester (CAPE) (which is an active compound of propolis) against herpes simplex type 1 and 2 was examined in cell culture. The advantage of microscopic FTIR spectroscopy over conventional FTIR spectroscopy is that it facilitates inspection of restricted regions of cell culture or tissue. Our results showed significant spectral differences at early stages of infection between infected and non-infected cells, and between infected cells treated with the used antiviral agent and those not treated. In infected cells, there was a considerable increase in phosphate levels. Our results show that treatment with used antiviral agent considerably abolish the spectral changes induced by the viral infection. In addition, it is possible to track by FTIR microscopy method the deferential effect of various doses of the drug.

  19. Design and development of antivirals and intervention strategies against human herpesviruses using high-throughput approach.

    Science.gov (United States)

    Hornig, Julia; McGregor, Alistair

    2014-08-01

    Although a number of antiviral agents are licensed for treatment of some human herpesvirus (HHV) infections, effective antiviral therapy is not available for all HHVs. Additional complications are associated with approved drugs, such as toxicity and side effects, and rise in drug-resistant strains is a driving force for new drug development. Success in HHV vaccine development is limited with only vaccines against varicella-zoster virus currently in use in the clinic. In vitro, in vivo and in silico high-throughput (HTP) approaches and innovative microfluidic systems will provide novel technologies to efficiently identify and evaluate new targets and antiherpetic compounds. Coupled with HTP strategies for manipulation of herpesvirus viral genomes, these strategies will greatly accelerate the development of future antivirals as well as candidate vaccine intervention strategies. The authors provide a brief overview of the herpesvirus family and associated diseases. Further, the authors discuss the approved and investigational antiherpetic drugs in the context of current HTP technologies. HTP technology such as microfluidic systems is crucial for the identification and validation of novel drug targets and next-generation antivirals. Current drug development is limited by the unavailability of HTP preclinical model systems. Specific advancement in the development of HTP animal-specific technology, applied in parallel, allows a more rapid evaluation of drugs at the preclinical stage. The advancement of HTP combinatorial drug therapy, especially 'Organ-on-a-Chip' approaches, will aid in the evaluation of future antiviral compounds and intervention strategies.

  20. Synergistic antiviral activity of gemcitabine and ribavirin against enteroviruses.

    Science.gov (United States)

    Kang, Hyunju; Kim, Chonsaeng; Kim, Dong-eun; Song, Jae-Hyoung; Choi, Miri; Choi, Kwangman; Kang, Mingu; Lee, Kyungjin; Kim, Hae Soo; Shin, Jin Soo; Kim, Janghwan; Han, Sang-Bae; Lee, Mi-Young; Lee, Su Ui; Lee, Chong-Kyo; Kim, Meehyein; Ko, Hyun-Jeong; van Kuppeveld, Frank J M; Cho, Sungchan

    2015-12-01

    Enteroviruses are major causative agents of various human diseases, and some of them are currently considered to be an enormous threat to public health. However, no effective therapy is currently available for the treatment of these infections. We identified gemcitabine, a nucleoside-analog drug used for cancer treatment, from a screen of bioactive chemicals as a novel inhibitor of coxsackievirus B3 (CVB3) and enterovirus 71 (EV71). Gemcitabine potently inhibited the proliferation of CVB3 and EV71, as well as the replication of CVB3 and EV71 replicons, in cells with a low micromolar IC50 (1-5 μM). Its strong inhibitory effect was also observed in cells infected with human rhinoviruses, demonstrating broad-spectrum antiviral effects on enteroviruses. Mechanistically, an extensive analysis excluded the involvement of 2C, 3A, IRES-dependent translation, and also that of polyprotein processing in the antiviral effects of gemcitabine. Importantly, gemcitabine in combination with ribavirin, an antiviral drug currently being used against a few RNA viruses, exhibited a synergistic antiviral effect on the replication of CVB3 and EV71 replicons. Consequently, our results clearly demonstrate a new indication for gemcitabine as an effective broad-spectrum inhibitor of enteroviruses and strongly suggest a new therapeutic strategy using gemcitabine alone or in combination with ribavirin for the treatment of various diseases associated with enterovirus infection. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Development and characterization of hepatitis C virus genotype 1-7 cell culture systems: role of CD81 and scavenger receptor class B type I and effect of antiviral drugs

    DEFF Research Database (Denmark)

    Gottwein, Judith M; Scheel, Troels K H; Jensen, Tanja B

    2009-01-01

    -6 viruses had similar spread kinetics, intracellular Core, NS5A, and lipid amounts, and colocalization of Core and NS5A with lipids. Treatment with interferon-alpha2b but not ribavirin or amantadine showed a significant antiviral effect. Infection with all genotypes could be blocked by specific antibodies...... against the putative coreceptors CD81 and scavenger receptor class B type I in a dose-dependent manner. Finally, neutralizing antibodies in selected chronic phase HCV sera had differential effects against genotype 1-7 viruses. Conclusion: We completed and characterized a panel of JFH1-based cell culture...... systems of all seven major HCV genotypes and important subtypes and used these viruses in comparative studies of antivirals, HCV receptor interaction, and neutralizing antibodies....

  2. Antiviral treatment for Bell's palsy (idiopathic facial paralysis).

    Science.gov (United States)

    Gagyor, Ildiko; Madhok, Vishnu B; Daly, Fergus; Somasundara, Dhruvashree; Sullivan, Michael; Gammie, Fiona; Sullivan, Frank

    2015-11-09

    Corticosteroids are widely used in the treatment of idiopathic facial paralysis (Bell's palsy), but the effectiveness of additional treatment with an antiviral agent is uncertain. Significant morbidity can be associated with severe cases of Bell's palsy. This review was first published in 2001 and revised several times, most recently in 2009. This version replaces an update of the review in Issue 7 of the Cochrane Library subsequently withdrawn because of an ongoing investigation into the reliability of data from an included study. To assess the effects of antiviral treatments alone or in combination with any other therapy for Bell's palsy. On 7 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, DARE, NHS EED, and HTA. We also reviewed the bibliographies of the identified trials and contacted trial authors and known experts in the field and relevant drug companies to identify additional published or unpublished data. We searched clinical trials registries for ongoing studies. We considered randomised controlled trials or quasi-randomised controlled trials of antivirals with and without corticosteroids versus control therapies for the treatment of Bell's palsy. We excluded trials that had a high risk of bias in several domains. Pairs of authors independently assessed trials for relevance, eligibility, and risk of bias, using standard Cochrane procedures. Ten trials, including 2280 participants, met the inclusion criteria and are included in the final analysis. Some of the trials were small, and a number were at high or unclear risk of bias. Other trials did not meet current best standards in allocation concealment and blinding. Incomplete recoveryWe found a significant benefit from adding antivirals to corticosteroids in comparison with corticosteroids alone for people with Bell's palsy (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.39 to 0.97, n = 1315). For people with severe Bell

  3. Antiviral Polymer Therapeutics

    DEFF Research Database (Denmark)

    Smith, Anton Allen Abbotsford

    2014-01-01

    polymerized in a controlled manner with carrier monomers of historically proven biocompatible polymers. The carrier polymers, the loading of ribavirin as well as the size of the polymer were varied systematically with the aid of an automated synthesis platform. These polymers were tested in a cellular assay...... of reversible-addition-fragmentation chain transfer polymerization, which not only controls the size of polymer, but also allows the introduction of a terminal amine on the polymer which can be used for further conjugation. This has allowed for not only fluorescent labeling of the polymer, but also protein......The field of drug delivery is in essence an exercise in engineered pharmacokinetics. Methods of doing so have been developed through the introduction of a vehicle carrying the drug, either by encapsulation or covalent attachment. The emergence of polymer therapeutics in anticancer therapy has...

  4. Antiviral Effect Assay of Aqueous Extract of Echium Amoenum-L against HSV-1

    Directory of Open Access Journals (Sweden)

    Malihe Farahani

    2013-08-01

    Full Text Available Background: Medicinal plants have been used for different diseases in past. There is an increasing need for substances with antiviral activity since the treatment of viral infections with the available antiviral drugs often leads to the problem of viral resistance. Therefore in the present study Echium amoenum L plant with ethnomedical background was screened for antiviral activity against HSV-1 in different times. Materials and Methods: Flower part of Echium amoenum L plant collected from Iran was extracted with different methods to obtain crude aqueous extract. This extract was screened for its cytotoxicity against Hep II cell line by CPE assay. Antiviral properties of the plant extract were determined by cytopathic effect inhibition assay.Results: Echium amoenum L extract exhibited significant antiviral activity at non toxic concentrations to the cell line used. Findings indicated that plant extract has the most antiviral activity when it used an hour after virus inoculation.Conclusion: Echium amoenum L plant had not toxic effect at highest concentrations to the cell lines used and showed the most antiviral activity when it used an hour after virus inoculation. Further research is needed to elucidate the active constituents of this plant which may be useful in the development of new and effective antiviral agents.

  5. Monitoring and Characterization of Oseltamivir-Resistant Pandemic (H1N1) 2009 Virus, Japan, 2009–2010

    Science.gov (United States)

    Ujike, Makoto; Ejima, Miho; Anraku, Akane; Shimabukuro, Kozue; Obuchi, Masatsugu; Kishida, Noriko; Hong, Xu; Takashita, Emi; Fujisaki, Seiichiro; Yamashita, Kazuyo; Horikawa, Hiroshi; Kato, Yumiko; Oguchi, Akio; Fujita, Nobuyuki; Tashiro, Masato

    2011-01-01

    To monitor and characterize oseltamivir-resistant (OR) pandemic (H1N1) 2009 virus with the H275Y mutation, we analyzed 4,307 clinical specimens from Japan by neuraminidase (NA) sequencing or inhibition assay; 61 OR pandemic (H1N1) 2009 viruses were detected. NA inhibition assay and M2 sequencing indicated that OR pandemic (H1N1) 2009 virus was resistant to M2 inhibitors, but sensitive to zanamivir. Full-genome sequencing showed OR and oseltamivir-sensitive (OS) viruses had high sequence similarity, indicating that domestic OR virus was derived from OS pandemic (H1N1) 2009 virus. Hemagglutination inhibition test demonstrated that OR and OS pandemic (H1N1) 2009 viruses were antigenically similar to the A/California/7/2009 vaccine strain. Of 61 case-patients with OR viruses, 45 received oseltamivir as treatment, and 10 received it as prophylaxis, which suggests that most cases emerged sporadically from OS pandemic (H1N1) 2009, due to selective pressure. No evidence of sustained spread of OR pandemic (H1N1) 2009 was found in Japan; however, 2 suspected incidents of human-to-human transmission were reported. PMID:21392439

  6. A non-biological method for screening active components against influenza virus from traditional Chinese medicine by coupling a LC column with oseltamivir molecularly imprinted polymers.

    Directory of Open Access Journals (Sweden)

    Ya-Jun Yang

    Full Text Available To develop a non-biological method for screening active components against influenza virus from traditional Chinese medicine (TCM extraction, a liquid chromatography (LC column prepared with oseltamivir molecularly imprinted polymer (OSMIP was employed with LC-mass spectrometry (LC-MS. From chloroform extracts of compound TCM liquid preparation, we observed an affinitive component m/z 249, which was identified to be matrine following analysis of phytochemical literatures, OSMIP-LC column on-line of control compounds and MS/MS off-line. The results showed that matrine had similar bioactivities with OS against avian influenza virus H9N2 in vitro for both alleviating cytopathic effect and hemagglutination inhibition and that the stereostructures of these two compounds are similar while their two-dimensional structures were different. In addition, our results suggested that the bioactivities of those affinitive compounds were correlated with their chromatographic behaviors, in which less difference of the chromatographic behaviors might have more similar bioactivities. This indicates that matrine is a potential candidate drug to prevent or cure influenza for human or animal. In conclusion, the present study showed that molecularly imprinted polymers can be used as a non-biological method for screening active components against influenza virus from TCM.

  7. Assessment of the Antiviral Properties of Recombinant Porcine SP-D against Various Influenza A Viruses In Vitro

    NARCIS (Netherlands)

    Hillaire, M.L.B.|info:eu-repo/dai/nl/341413933; van Eijk, M.|info:eu-repo/dai/nl/255160216; Trierum, S.E.; van Riel, D.; Saelens, X.; Romijn, R.A.P.|info:eu-repo/dai/nl/26228359X; Hemrika, W.|info:eu-repo/dai/nl/121631362; Fouchier, R.A.M.; Kuiken, T.; Osterhaus, A.D.M.E.|info:eu-repo/dai/nl/074960172; Haagsman, H.P.|info:eu-repo/dai/nl/069273278; Rimmelzwaan, G.F.

    2011-01-01

    The emergence of influenza viruses resistant to existing classes of antiviral drugs raises concern and there is a need for novel antiviral agents that could be used therapeutically or prophylacticaly. Surfactant protein D (SP-D) belongs to the family of Ctype lectins which are important effector

  8. Assessment of the antiviral properties of recombinant porcine SP-D against various influenza A viruses in vitro

    NARCIS (Netherlands)

    M.L.B. Hillaire (Marine); M. van Eijk (Martin); S.E. Trierum (Stella); D.A.J. van Riel (Debby); X. Saelens (Xavier); R.A. Romijn (Roland); W. Hemrika (Wieger); R.A.M. Fouchier (Ron); T. Kuiken (Thijs); A.D.M.E. Osterhaus (Albert); H.P. Haagsman (Henk); G.F. Rimmelzwaan (Guus)

    2011-01-01

    textabstractThe emergence of influenza viruses resistant to existing classes of antiviral drugs raises concern and there is a need for novel antiviral agents that could be used therapeutically or prophylacticaly. Surfactant protein D (SP-D) belongs to the family of C-type lectins which are important

  9. The future of antiviral immunotoxins

    DEFF Research Database (Denmark)

    Spiess, K.; Høy Jakobsen, Mette; Kledal, Thomas N

    2016-01-01

    There is a constant need for new therapeutic interventions in a wide range of infectious diseases. Over the past few years, the immunotoxins have entered the stage as promising antiviral treatments. Immunotoxins have been extensively explored in cancer treatment and have achieved FDA approval...

  10. Interfering antiviral immunity: application, subversion, hope?

    Science.gov (United States)

    Manjunath, N; Kumar, Priti; Lee, Sang Kyung; Shankar, Premlata

    2006-07-01

    RNA interference (RNAi), initially recognized as a natural antiviral mechanism in plants, has rapidly emerged as an invaluable tool to suppress gene expression in a sequence-specific manner in all organisms, including mammals. Its potential to inhibit the replication of a variety of viruses has been demonstrated in vitro and in vivo in mouse and monkey models. These results have generated profound interest in the use of this technology as a potential treatment strategy for viral infections for which vaccines and drugs are unavailable or inadequate. In this review, we discuss the progress made within the past 2-3 years towards harnessing the potential of RNAi for clinical application in viral infections and the hurdles that have yet to be overcome.

  11. Antiviral effect of lithium chloride on infection of cells by canine parvovirus.

    Science.gov (United States)

    Zhou, Pei; Fu, Xinliang; Yan, Zhongshan; Fang, Bo; Huang, San; Fu, Cheng; Hong, Malin; Li, Shoujun

    2015-11-01

    Canine parvovirus type 2 causes significant viral disease in dogs, with high morbidity, high infectivity, and high mortality. Lithium chloride is a potential antiviral drug for viruses. We determined the antiviral effect of Lithium Chloride on canine parvovirus type 2 in feline kidney cells. The viral DNA and proteins of canine parvovirus were suppressed in a dose-dependent manner by lithium chloride. Further investigation verified that viral entry into cells was inhibited in a dose-dependent manner by lithium chloride. These results indicated that lithium chloride could be a potential antiviral drug for curing dogs with canine parvovirus infection. The specific steps of canine parvovirus entry into cells that are affected by lithium chloride and its antiviral effect in vivo should be explored in future studies.

  12. Antiviral therapy for chronic hepatitis B: a review.

    Science.gov (United States)

    Hanazaki, Kazuhiro

    2004-03-01

    Chronic hepatitis B virus (HBV) infection is a well-recognized risk factor for the development of hepatocellular carcinoma (HCC), which is becoming a more prevalent clinical problem, especially in HBV-endemic areas. It is estimated that 1.25 million people in the United States and more than 300 million people worldwide are chronically infected with HBV. Despite the introduction of universal vaccination against hepatitis B in over 100 countries, persistent HBV infection is still a serious problem worldwide, causing an estimated annual death rate of one million. It may take several decades until the effect of vaccination will be translated into reduced transmission and morbidity. Meanwhile, patients with persistent HBV infection require better antiviral therapeutic modalities than are currently available. It is well accepted that antiviral therapy for chronic hepatitis B is effective to improve prognosis of patients with HBV by preventing development of hepatitis state and HCC. The therapeutic endpoints for hepatitis B treatment are: 1) sustained suppression of HBV replication, as indicated by HBsAg and HBeAg loss, 2) decrease of serum HBV DNA of an undetectable level by a non-PCR method, 3) remission of disease, as shown by normalization of ALT, 4) improvement in liver histology, and 5) reduction of the acute exacerbation, cirrhosis, and HCC. In the present, the antiviral treatment of hepatitis B consists of either interferon alpha or oral lamivudine alone or in combination with existing therapy. Each major antiviral drug of interferon alpha and lamivudine has pros and cons, and effect of combination therapy of both drugs is also still limited. More powerful and safe new antiviral therapies are required to achieve final goal of these therapeutic endpoints. Management of chronic hepatitis B requires significant knowledge of approved pharmacotherapeutic agents and their limitations. Therapeutic options for managing hepatitis infection after liver transplantation (LT

  13. Antibody administration in experimental influenza increases survival and enhances the effect of oseltamivir

    DEFF Research Database (Denmark)

    Pourroy, Brit Naldahl; Nielsen, Lars Peter; Kolmos, Hans Jørn

    2012-01-01

    Anti-viral chemotherapy plays an important part in treating and preventing influenza illness. However, its effectiveness in severe infections can be debated and a reoccurring problem is the emergence of resistant virus. Passive immunisation has for a long time been and is still used for prophylax...

  14. Validated spectrophotometric methods for the evaluation of Oseltamivir counterfeit pharmaceutical capsules

    Directory of Open Access Journals (Sweden)

    Rasha M. Youssef

    2014-06-01

    Full Text Available Four rapid, reliable and economical spectrophotometric methods have been established for the quantitative determination of Oseltamivir phosphate (OST without the interference of ascorbic acid (ASC found in some of its counterfeit capsules. The first method involves the use of derivative spectrophotometry with the zero-crossing technique where OST was easily determined using its 1D (Δλ = 3 at 219 nm. The second method is based on a first-order derivative ratio spectrophotometry (1DD, Δλ = 5 where 218 nm was selected for its quantification, while the third method applies a more advanced spectrophotometric method based on the ratio difference spectrophotometry (RD in which the difference in absorbance ratio was measured between 217 and 210 nm. In the fourth method, difference spectrophotometric method (ΔA is applied by subtracting absorbance at 252 from that at 263 nm where the difference in absorbance was zero for ASC. The proposed methods were validated for linearity, accuracy, precision and selectivity. Synthetic mixtures of different proportions and commercial capsules were assayed by the proposed methods and the results revealed good accuracy and repeatability of the developed methods.

  15. Treatment of antiviral-resistant recurrent erythema multiforme with dapsone.

    Science.gov (United States)

    Oak, Allen S W; Seminario-Vidal, Lucia; Sami, Naveed

    2017-03-01

    Recurrent erythema multiforme (REM) is a chronic disease characterized by frequent episodes of target cutaneous lesions in an acral distribution. Conventional treatment includes systemic corticosteroids and antiviral therapy. The aim of this study was to evaluate dapsone as a potential steroid sparing-agent for the treatment of REM after a failed trial of at least one antiviral therapy (acyclovir, famciclovir, or valacyclovir). A retrospective chart review was conducted on thirteen patients with a diagnosis of REM who underwent treatment with dapsone after failing at least one antiviral therapy. Out of 13 patients, 6 showed complete response (CR) and 5 showed partial response (PR). The underlying cause was identified in 5 patients with all showing at least PR. Adverse effects, observed in 4 patients, included fatigue, macrocytic anemia, anxiety, insomnia and involuntary movements, and drug-induced lupus erythematosus. A continuous course of dapsone, titrated up from 25 mg/day to a dose at which clinical improvement is seen with acceptable patient tolerance, is a viable steroid sparing-agent for REM treatment after a failed trial of antiviral therapy. © 2016 Wiley Periodicals, Inc.

  16. Antiviral Activities of Several Oral Traditional Chinese Medicines against Influenza Viruses.

    Science.gov (United States)

    Ma, Lin-Lin; Ge, Miao; Wang, Hui-Qiang; Yin, Jin-Qiu; Jiang, Jian-Dong; Li, Yu-Huan

    2015-01-01

    Influenza is still a serious threat to human health with significant morbidity and mortality. The emergence of drug-resistant influenza viruses poses a great challenge to existing antiviral drugs. Traditional Chinese medicines (TCMs) may be an alternative to overcome the challenge. Here, 10 oral proprietary Chinese medicines were selected to evaluate their anti-influenza activities. These drugs exhibit potent inhibitory effects against influenza A H1N1, influenza A H3N2, and influenza B virus. Importantly, they demonstrate potent antiviral activities against drug-resistant strains. In the study of mechanisms, we found that Xiaoqinglong mixture could increase antiviral interferon production by activating p38 MAPK, JNK/SAPK pathway, and relative nuclear transcription factors. Lastly, our studies also indicate that some of these medicines show inhibitory activities against EV71 and CVB strains. In conclusion, the 10 traditional Chinese medicines, as kind of compound combination medicines, show broad-spectrum antiviral activities, possibly also including inhibitory activities against strains resistant to available antiviral drugs.

  17. Antiviral strategies for emerging influenza viruses in remote communities.

    Directory of Open Access Journals (Sweden)

    Marek Laskowski

    Full Text Available Due to the lack of timely access to resources for critical care, strategic use of antiviral drugs is crucial for mitigating the impact of novel influenza viruses with pandemic potential in remote and isolated communities. We sought to evaluate the effect of antiviral treatment and prophylaxis of close contacts in a Canadian remote northern community.We used an agent-based, discrete-time simulation model for disease spread in a remote community, which was developed as an in-silico population using population census data. Relative and cumulative age-specific attack rates, and the total number of infections in simulated model scenarios were obtained.We found that early initiation of antiviral treatment is more critical for lowering attack rates in a remote setting with a low population-average age compared to an urban population. Our results show that a significant reduction in the relative, age-specific attack rates due to increasing treatment coverage does not necessarily translate to a significant reduction in the overall arrack rate. When treatment coverage varies from low to moderate, targeted prophylaxis has a very limited impact in reducing attack rates and should be offered at a low level (below 10% to avoid excessive waste of drugs.In contrast to previous work, for conservative treatment coverages, our results do not provide any convincing evidence for the implementation of targeted prophylaxis. The findings suggest that public health strategies in remote communities should focus on the wider availability (higher coverage and timely distribution of antiviral drugs for treatment of clinically ill individuals.

  18. Escape Mutations in NS4B Render Dengue Virus Insensitive to the Antiviral Activity of the Paracetamol Metabolite AM404.

    Science.gov (United States)

    van Cleef, Koen W R; Overheul, Gijs J; Thomassen, Michael C; Marjakangas, Jenni M; van Rij, Ronald P

    2016-04-01

    Despite the enormous disease burden associated with dengue virus infections, a licensed antiviral drug is lacking. Here, we show that the paracetamol (acetaminophen) metabolite AM404 inhibits dengue virus replication. Moreover, we find that mutations in NS4B that were previously found to confer resistance to the antiviral compounds NITD-618 and SDM25N also render dengue virus insensitive to AM404. Our work provides further support for NS4B as a direct or indirect target for antiviral drug development. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  19. In silico design of cyclic peptides as influenza virus, a subtype H1N1 ...

    African Journals Online (AJOL)

    Vaccine treatment is useless for controlling this disease because of the occurrence of mutation in the influenza virus. Influenza virus is also resistant to some antiviral drugs like oseltamivir and zanamivir, which inhibit neuraminidase. Another solution for controlling this virus is to find new design for antiviral drugs. Cyclic ...

  20. A Modified P1 Moiety Enhances in vitro Antiviral Activity against Various Multi-Drug-Resistant HIV-1 Variants and in vitro CNS Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413

    Energy Technology Data Exchange (ETDEWEB)

    Amano, Masayuki; Salcedo-Gómez, Pedro Miguel; Zhao, Rui; Yedidi, Ravikiran S.; Das, Debananda; Bulut, Haydar; Delino, Nicole S.; Sheri, Venkata Reddy; Ghosh, Arun K.; Mitsuya, Hiroaki (Kumamoto); (NIH); (Purdue)

    2016-09-12

    We here report that GRL-10413, a novel non-peptidic HIV-1 protease inhibitor (PI) containing a modified P1 moiety and a sulfonamide isostere, is highly active against laboratory HIV-1 strains and primary clinical isolates (EC50: 0.00035 - 0.0018 μM) with minimal cytotoxicity (CC50: 35.7 μM). GRL-10413 blocked the infectivity and replication of HIV-1NL4-3variants selected by up to 5 μM concentrations of atazanavir, lopinavir, or amprenavir (EC50: 0.0021 - 0.0023 μM). GRL-10413 also maintained its strong antiviral activity against multi-drug-resistant clinical HIV-1 variants isolated from patients, who no longer responded to various antiviral regimens after long-term antiretroviral therapy. The development of resistance against GRL-10413 was significantly delayed compared to that of APV. In addition, GRL-10413 showed a favorable central nervous system (CNS) penetration property as assessed with anin vitroblood brain barrier (BBB) reconstruction system. Analysis of the crystal structure of HIV-1 protease in complex with GRL-10413 demonstrated that the modified P1 moiety of GRL-10413 has a greater hydrophobic surface area and makes greater van der Waals contacts with active-site amino acids of protease than in the case of darunavir. Moreover, the chlorine substituent in the P1 moiety interacts with protease in two distinct configurations. The present data demonstrate that GRL-10413 has desirable features for treating patients infected with wild-type and/or multi-drug-resistant HIV-1 variants with favorable CNS-penetration capability and that the newly modified P1-moiety may confer desirable features in designing novel anti-HIV-1 PIs.

  1. Sequence-Specific Modifications Enhance the Broad-Spectrum Antiviral Response Activated by RIG-I Agonists

    Science.gov (United States)

    Chiang, Cindy; Beljanski, Vladimir; Yin, Kevin; Olagnier, David; Ben Yebdri, Fethia; Steel, Courtney; Goulet, Marie-Line; DeFilippis, Victor R.; Streblow, Daniel N.; Haddad, Elias K.; Trautmann, Lydie; Ross, Ted; Lin, Rongtuan

    2015-01-01

    ABSTRACT The cytosolic RIG-I (retinoic acid-inducible gene I) receptor plays a pivotal role in the initiation of the immune response against RNA virus infection by recognizing short 5′-triphosphate (5′ppp)-containing viral RNA and activating the host antiviral innate response. In the present study, we generated novel 5′ppp RIG-I agonists of varieous lengths, structures, and sequences and evaluated the generation of the antiviral and inflammatory responses in human epithelial A549 cells, human innate immune primary cells, and murine models of influenza and chikungunya viral pathogenesis. A 99-nucleotide, uridine-rich hairpin 5′pppRNA termed M8 stimulated an extensive and robust interferon response compared to other modified 5′pppRNA structures, RIG-I aptamers, or poly(I·C). Interestingly, manipulation of the primary RNA sequence alone was sufficient to modulate antiviral activity and inflammatory response, in a manner dependent exclusively on RIG-I and independent of MDA5 and TLR3. Both prophylactic and therapeutic administration of M8 effectively inhibited influenza virus and dengue virus replication in vitro. Furthermore, multiple strains of influenza virus that were resistant to oseltamivir, an FDA-approved therapeutic treatment for influenza, were highly sensitive to inhibition by M8. Finally, prophylactic M8 treatment in vivo prolonged survival and reduced lung viral titers of mice challenged with influenza virus, as well as reducing chikungunya virus-associated foot swelling and viral load. Altogether, these results demonstrate that 5′pppRNA can be rationally designed to achieve a maximal RIG-I-mediated protective antiviral response against human-pathogenic RNA viruses. IMPORTANCE The development of novel therapeutics to treat human-pathogenic RNA viral infections is an important goal to reduce spread of infection and to improve human health and safety. This study investigated the design of an RNA agonist with enhanced antiviral and inflammatory

  2. Systematic review of influenza resistance to the neuraminidase inhibitors

    Directory of Open Access Journals (Sweden)

    Boivin Guy

    2011-05-01

    Full Text Available Abstract Background Antivirals play a critical role in the prevention and the management of influenza. One class of antivirals, neuraminidase inhibitors (NAIs, is effective against all human influenza viruses. Currently there are two NAI drugs which are licensed worldwide: oseltamivir (Tamiflu® and zanamivir (Relenza®; and two drugs which have received recent approval in Japan: peramivir and laninamivir. Until recently, the prevalence of antiviral resistance has been relatively low. However, almost all seasonal H1N1 strains that circulated in 2008-09 were resistant to oseltamivir whereas about 1% of tested 2009 pandemic H1N1 viruses were found to be resistant to oseltamivir. To date, no studies have demonstrated widespread resistance to zanamivir. It seems likely that the literature on antiviral resistance associated with oseltamivir as well as zanamivir is now sufficiently comprehensive to warrant a systematic review. The primary objectives were to systematically review the literature to determine the incidence of resistance to oseltamivir, zanamivir, and peramivir in different population groups as well as assess the clinical consequences of antiviral resistance. Methods We searched MEDLINE and EMBASE without language restrictions in September 2010 to identify studies reporting incidence of resistance to oseltamivir, zanamivir, and peramivir. We used forest plots and meta-analysis of incidence of antiviral resistance associated with the three NAIs. Subgroup analyses were done across a number of population groups. Meta-analysis was also performed to evaluate associations between antiviral resistance and clinical complications and symptoms. Results We identified 19 studies reporting incidence of antiviral resistance. Meta-analysis of 15 studies yielded a pooled incidence rate for oseltamivir resistance of 2.6% (95%CI 0.7% to 5.5%. The incidence rate for all zanamivir resistance studies was 0%. Only one study measured incidence of antiviral

  3. Spectral characterisation, antiviral activities, in silico ADMET and molecular docking of the compounds isolated from Tectona grandis to chikungunya virus.

    Science.gov (United States)

    K, Sangeetha; Purushothaman, Indu; S, Rajarajan

    2017-03-01

    Chikungunya infection is treated symptomatically with antipyretics and anti-inflammatory drugs without any specific antiviral drug till date. The lack of an approved antiviral drug and the emergence of virulent strains after 2006 epidemics emphasize the need for the development of potential antiviral drugs to Chikungunya virus. Hence, we studied the antiviral activity of the extracts and compounds isolated from Tectona grandis leaves to both the Asian and East central South African strains of Chikungunya virus. Five compounds were isolated from the ethanolic extract of Tectona grandis by bioactivity guided fractionation followed by Spectral Characterisation through GC-MS and NMR spectroscopy and investigated for the antiviral activity. Also in silico ADMET and Molecular Docking of the characterised compounds against the structural and non structural proteins of Chikungunya virus were performed. The characterised compound Benzene-1-carboxylic acid hexadeconate was effective at IC 50 3.036μg/ml (7.5μM) and 76.46μg/ml (189.02μM) to Asian and ECSA strain of CHIKV respectively. The compound showed desirable pharmacokinetic properties and significant molecular interactions with the E1 protein of Chikungunya virus by in silico analysis. Thus Benzene-1-carboxylic acid-2-hexadeconate isolated from Tectona grandis was found to be a promising drug candidate to both the Asian and ECSA strains of Chikungunya virus with high selectivity indices in comparison to the reference RNA antiviral drug Ribavirin. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  4. Cost-utility analysis of antiviral use under pandemic influenza using a novel approach - linking pharmacology, epidemiology and heath economics.

    Science.gov (United States)

    Wu, D B C; Chaiyakunapruk, N; Pratoomsoot, C; Lee, K K C; Chong, H Y; Nelson, R E; Smith, P F; Kirkpatrick, C M; Kamal, M A; Nieforth, K; Dall, G; Toovey, S; Kong, D C M; Kamauu, A; Rayner, C R

    2018-03-01

    Simulation models are used widely in pharmacology, epidemiology and health economics (HEs). However, there have been no attempts to incorporate models from these disciplines into a single integrated model. Accordingly, we explored this linkage to evaluate the epidemiological and economic impact of oseltamivir dose optimisation in supporting pandemic influenza planning in the USA. An HE decision analytic model was linked to a pharmacokinetic/pharmacodynamics (PK/PD) - dynamic transmission model simulating the impact of pandemic influenza with low virulence and low transmissibility and, high virulence and high transmissibility. The cost-utility analysis was from the payer and societal perspectives, comparing oseltamivir 75 and 150 mg twice daily (BID) to no treatment over a 1-year time horizon. Model parameters were derived from published studies. Outcomes were measured as cost per quality-adjusted life year (QALY) gained. Sensitivity analyses were performed to examine the integrated model's robustness. Under both pandemic scenarios, compared to no treatment, the use of oseltamivir 75 or 150 mg BID led to a significant reduction of influenza episodes and influenza-related deaths, translating to substantial savings of QALYs. Overall drug costs were offset by the reduction of both direct and indirect costs, making these two interventions cost-saving from both perspectives. The results were sensitive to the proportion of inpatient presentation at the emergency visit and patients' quality of life. Integrating PK/PD-EPI/HE models is achievable. Whilst further refinement of this novel linkage model to more closely mimic the reality is needed, the current study has generated useful insights to support influenza pandemic planning.

  5. Antiviral activity of lanatoside C against dengue virus infection.

    Science.gov (United States)

    Cheung, Yan Yi; Chen, Karen Caiyun; Chen, Huixin; Seng, Eng Khuan; Chu, Justin Jang Hann

    2014-11-01

    Dengue infection poses a serious threat globally due to its recent rapid spread and rise in incidence. Currently, there is no approved vaccine or effective antiviral drug for dengue virus infection. In response to the urgent need for the development of an effective antiviral for dengue virus, the US Drug Collection library was screened in this study to identify compounds with anti-dengue activities. Lanatoside C, an FDA approved cardiac glycoside was identified as a candidate anti-dengue compound. Our data revealed that lanatoside C has an IC50 of 0.19μM for dengue virus infection in HuH-7 cells. Dose-dependent reduction in dengue viral RNA and viral proteins synthesis were also observed upon treatment with increasing concentrations of lanatoside C. Time of addition study indicated that lanatoside C inhibits the early processes of the dengue virus replication cycle. Furthermore, lanatoside C can effectively inhibit all four serotypes of dengue virus, flavivirus Kunjin, alphavirus Chikungunya and Sindbis virus as well as the human enterovirus 71. These findings suggest that lanatoside C possesses broad spectrum antiviral activity against several groups of positive-sense RNA viruses. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. In vitro evaluation of marine-microorganism extracts for anti-viral activity

    Directory of Open Access Journals (Sweden)

    Yasuhara-Bell Jarred

    2010-08-01

    Full Text Available Abstract Viral-induced infectious diseases represent a major health threat and their control remains an unachieved goal, due in part to the limited availability of effective anti-viral drugs and measures. The use of natural products in drug manufacturing is an ancient and well-established practice. Marine organisms are known producers of pharmacological and anti-viral agents. In this study, a total of 20 extracts from marine microorganisms were evaluated for their antiviral activity. These extracts were tested against two mammalian viruses, herpes simplex virus (HSV-1 and vesicular stomatitis virus (VSV, using Vero cells as the cell culture system, and two marine virus counterparts, channel catfish virus (CCV and snakehead rhabdovirus (SHRV, in their respective cell cultures (CCO and EPC. Evaluation of these extracts demonstrated that some possess antiviral potential. In sum, extracts 162M(4, 258M(1, 298M(4, 313(2, 331M(2, 367M(1 and 397(1 appear to be effective broad-spectrum antivirals with potential uses as prophylactic agents to prevent infection, as evident by their highly inhibitive effects against both virus types. Extract 313(2 shows the most potential in that it showed significantly high inhibition across all tested viruses. The samples tested in this study were crude extracts; therefore the development of antiviral application of the few potential extracts is dependent on future studies focused on the isolation of the active elements contained in these extracts.

  7. Antiviral activity of gemcitabine against human rhinovirus in vitro and in vivo.

    Science.gov (United States)

    Song, Jae-Hyoung; Kim, Seong-Ryeol; Heo, Eun-Young; Lee, Jae-Young; Kim, Dong-Eun; Cho, Sungchan; Chang, Sun-Young; Yoon, Byung-Il; Seong, Jeongmin; Ko, Hyun-Jeong

    2017-09-01

    Rhinovirus, a major causative agent of the common cold, is associated with exacerbation of asthma and chronic obstructive pulmonary disease. Currently, there is no antiviral treatment or vaccine for human rhinovirus (HRV). Gemcitabine (2',2'-difluorodeoxycytidine, dFdC) is a deoxycytidine analog with antiviral activity against rhinovirus, as well as enterovirus 71, in vitro. However, the antiviral effects of gemcitabine in vivo have not been investigated. In the current study, we assessed whether gemcitabine mediated antiviral effects in the murine HRV infection model. Intranasal administration of gemcitabine significantly lowered pulmonary viral load and inflammation by decreasing proinflammatory cytokines, including TNF-α and IL-1β, and reduction in the number of lung-infiltrating lymphocytes. Interestingly, we found that the addition of UTP and CTP significantly attenuated the antiviral activity of gemcitabine. Thus the limitation of UTP and CTP by the addition of gemcitabine may inhibit the viral RNA synthesis. These results suggest that gemcitabine, an antineoplastic drug, can be repositioned as an antiviral drug to inhibit HRV infection. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Modelling viral infections using zebrafish: Innate immune response and antiviral research.

    Science.gov (United States)

    Varela, Mónica; Figueras, Antonio; Novoa, Beatriz

    2017-03-01

    Zebrafish possess a highly developed immune system that is remarkably similar to the human one. Therefore, it is expected that the majority of the signalling pathways and molecules involved in the immune response of mammals exist and behave similarly in fish. The innate antiviral response depends on the recognition of viral components by host cells. Pattern recognition receptors initiate antimicrobial defence mechanisms via several well-conserved signalling pathways. In this paper, we review current knowledge of the antiviral innate immune response in zebrafish by considering the main molecules that have been characterized and the infection models used for the in vivo study of the antiviral innate immune response. We next summarize published studies in which larval and adult zebrafish were used to study viral diseases of fish, then provide a similar review of studies of human viral diseases in zebrafish and experience with antiviral drug screening in this model organism. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Historical Perspectives in the Development of Antiviral Agents Against Poxviruses

    Directory of Open Access Journals (Sweden)

    Erik De Clercq

    2010-06-01

    Full Text Available The poxvirus vaccinia virus (VV served as the model virus for which the first antivirals, the thiosemicarbazones, were identified. This dates back to 1950; and, although there is at present no single antiviral drug specifically licensed for the chemotherapy or -prophylaxis of poxvirus infections, numerous candidate compounds have been described over the past 50 years. These compounds include interferon and inducers thereof (i.e., polyacrylic acid, 5-substituted 2’-deoxyuridines (i.e., idoxuridine, IMP dehydrogenase inhibitors, S-adenosylhomocysteine hydrolase inhibitors, acyclic nucleoside phosphonates (such as cidofovir and alkoxyalkyl prodrugs thereof (such as CMX001, viral egress inhibitors (such as tecovirimat, and cellular kinase inhibitors (such as imatinib.

  10. Genetic Consequences of Antiviral Therapy on HIV-1

    Directory of Open Access Journals (Sweden)

    Miguel Arenas

    2015-01-01

    Full Text Available A variety of enzyme inhibitors have been developed in combating HIV-1, however the fast evolutionary rate of this virus commonly leads to the emergence of resistance mutations that finally allows the mutant virus to survive. This review explores the main genetic consequences of HIV-1 molecular evolution during antiviral therapies, including the viral genetic diversity and molecular adaptation. The role of recombination in the generation of drug resistance is also analyzed. Besides the investigation and discussion of published works, an evolutionary analysis of protease-coding genes collected from patients before and after treatment with different protease inhibitors was included to validate previous studies. Finally, the review discusses the importance of considering genetic consequences of antiviral therapies in models of HIV-1 evolution that could improve current genotypic resistance testing and treatments design.

  11. Development of oseltamivir and zanamivir resistance in influenza A(H1N1)pdm09 virus, Denmark, 2014

    DEFF Research Database (Denmark)

    Trebbien, Ramona; Pedersen, Svend Stenvang; Vorborg, Kristine

    2017-01-01

    Antiviral treatment of immunocompromised patients with prolonged influenza virus infection can lead to multidrug resistance. This study reveals the selection of antiviral resistance mutations in influenza A(H1N1)pdm09 virus in an immunocompromised patient during a 6-month period. The patient...

  12. New antivirals for the treatment of chronic hepatitis B.

    Science.gov (United States)

    Soriano, Vincent; Barreiro, Pablo; Benitez, Laura; Peña, Jose M; de Mendoza, Carmen

    2017-07-01

    Current treatment with oral nucleos(t)ides entecavir or tenofovir provide sustained suppression of HBV replication and clinical benefit in most chronic hepatitis B virus (HBV) infected persons. However, HBV rebound generally occurs upon drug discontinuation due to persistence of genomic HBV reservoirs as episomic cccDNA and chromosomic integrated HBV-DNA. There is renewed enthusiasm on HBV drug discovery following recent successes with antivirals for hepatitis C and immunotherapies for some cancers. Areas covered: New drugs that target distinct steps of the HBV life cycle are been developed, including inhibitors of viral entry, new polymerase inhibitors, capsid and assembly inhibitors, virus release blockers, and disruptors of cccDNA formation and transcription. Alongside these antivirals, agents that enhance anti-HBV specific immune responses are being tested, including TLR agonists, checkpoint inhibitors and therapeutic vaccines. Expert opinion: The achievement of a 'functional cure' for chronic HBV infection, with sustained HBsAg clearance and undetectable viremia once medications are stopped, represents the next step in the pace towards HBV elimination. Hopefully, the combination of new drugs that eliminate or functionally inactivate the genomic HBV reservoirs (cccDNA and integrated HBV-DNA) along with agents that enhance or activate immune responses against HBV will lead to a 'definitive cure' for chronic HBV infection.

  13. Antiviral lectins: Selective inhibitors of viral entry.

    Science.gov (United States)

    Mitchell, Carter A; Ramessar, Koreen; O'Keefe, Barry R

    2017-06-01

    Many natural lectins have been reported to have antiviral activity. As some of these have been put forward as potential development candidates for preventing or treating viral infections, we have set out in this review to survey the literature on antiviral lectins. The review groups lectins by structural class and class of source organism we also detail their carbohydrate specificity and their reported antiviral activities. The review concludes with a brief discussion of several of the pertinent hurdles that heterologous proteins must clear to be useful clinical candidates and cites examples where such studies have been reported for antiviral lectins. Though the clearest path currently being followed is the use of antiviral lectins as anti-HIV microbicides via topical mucosal administration, some investigators have also found systemic efficacy against acute infections following subcutaneous administration. Published by Elsevier B.V.

  14. Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial

    NARCIS (Netherlands)

    Sedyaningsih, Endang Rahayu; Malik, Moh Suhud; Setiawaty, Vivi; Trihono, Trihono; Burhan, Erlina; Aditama, Tjandra Yoga; Soepandi, Prijanti Z.; Partakusuma, Lia G.; Sutiyoso, Agung P.; Priatni, Ika; Bandung, Rumah Sakit Hasan Sadikan; Jusuf, Hadi; Pranggono, Emmy Hermiyanti; Soeroto, Arto Yuwono; Setiabudi, Djatnika; Somasetia, Dadang Hudaya; Sudarwati, Sri; Maskoen, Tini T.; Hartantri, Yovita; Parwati, Ida; Giriputro, Sardikin; Murniati, Dewi; Sirait, Sondang Maryutka; Soetanto, Tony; Sulastri, Sri; Agus, Rismali; Rusli, Adria; Wiweka, Sila; Wignall, Steve; Baird, Kevin; Safika, Iko; Sangsajja, Chariya; Manosuthi, Weerawat; Sutha, Patama; Chuchottaworn, Chareon; Sansayunh, Piamlarp; Bangpattanasiri, Kittima; Taylor, Walter R. J.; Stepniewska, Kasia; Fukuda, Caroline; Lindegardh, Niklas; White, Nicholas; Day, Nick; Chotpitayasunondh, Tawee; Suntarattiwong, Piyarat; Chantbuddhiwet, Umaporn; Netsawang, Supichaya; Chokephaibulkit, Kulkanya; Vanprapar, Nirun; Prasitsuebsai, Wasana; Wittawatmongkol, Orasri; Anekthananon, Thanomsak; Ratanasuwan, Winai; Rongrungruang, Yong; Puthavathana, Pilaipan; Tambyah, Paul A.; Leo, Yee-Sin; Fisher, Dale; Chai, Louis; Lee, Lawrence; Lin, Raymond; Minh, Ngo Ngoc Quang; Khanh, Truong Huu; Thoa, Le Phan Kim; Tuan, Le Anh; Thi, Tran My Dung; Ha, Lam Thi Thuy; Qui, Le Minh; Thinh, Le Quoc; Anh, Nguyen Ngoc Tu; Tuan, Tran Anh; Nhien, Trinh Hong; Phuong, Bui Pham; Qui, Phan Tu; Thy, Tieu Chau; Vu, Bui Xuan; Tinh, Le Binh Bao; Thanh, Dang Thi; Khanh, Vo Phuong; Viet, Do Chau; Thuy, Tran Thi; Bao, Vo Quoc; Trung, Le Nguyen Nhat; Thoa, Ho Thi Kim; Anh, Tran thi Ngoc; Loan, Tran Thi Thu; Huong, Tran Quynh; Le, Nguyen Thi Hanh; Viet, Ho Lu; Tuan, Ha Manh; Ha, Nguyen Van Vinh Chau; Truong, Nguyen Thanh; Thao, Le Thi Thu; Phong, Nguyen Thanh; Hien, Pham Tran Dieu; Men, Pham Thi Hai; Tam, Cao Thi; Diet, Tran Vinh; van Hao, Nguyen; van Kinh, Nguyen; Hien, Nguyen Duc; Ha, Nguyen Hong; van Tuyet, Hoang; Phuc, Nguyen Ngoc; Thai, Nguyen Quoc; Chinh, Luong Quoc; Cap, Nguyen Trung; Phu, Vu Dinh; Ninh, Tran Thi Hai; Trung, Nguyen Vu; Liem, Nguyen Thanh; Huy, Bui Vu; San, Luong Thi; Phuc, Phan Huu; Tuan, Ho Anh; Tung, Cao Viet; Thanh, Doan Thi Mai; Ngoc, Le Xuan; Hung, Pham Viet; Hung, Dau Viet; Hien, Pham Thu; Beigel, John; Polis, Michael; Higgs, Elizabeth; Ngan, Tran Thuy; Tham, Nguyen Thi; Tam, Duong Thi; Bkrong, Nguyen Thi Thuy Chinh; Uyen, Le Thi Tam; Hang, Vu thi Ty; Thanh, Tran Tan; Bryant, Juliet E.; Ha, Do Quang; Hien, Vo Minh; Nguyet, Lam An; Nhu, Le Nguyen Truc; Khuong, Huynh Duy; Stockwell, Elaine; Merson, Laura; Farrar, Jeremy J.; Hayden, Frederick; Hien, Tran Tinh; Fox, Annette; de Jong, Menno D.; Horby, Peter; Wertheim, Heiman L.; van Doorn, H. Rogier

    2013-01-01

    To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza. Double blind randomised trial. Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam. Patients aged ≥ 1 year admitted to hospital

  15. The RNA Template Channel of the RNA-Dependent RNA Polymerase as a Target for Development of Antiviral Therapy of Multiple Genera within a Virus Family

    NARCIS (Netherlands)

    van der Linden, Lonneke; Vives-Adrián, Laia; Selisko, Barbara; Ferrer-Orta, Cristina; Liu, Xinran; Lanke, Kjerstin; Ulferts, Rachel; De Palma, Armando M; Tanchis, Federica; Goris, Nesya; Lefebvre, David; De Clercq, Kris; Leyssen, Pieter; Lacroix, Céline; Pürstinger, Gerhard; Coutard, Bruno; Canard, Bruno; Boehr, David D; Arnold, Jamie J; Cameron, Craig E; Verdaguer, Nuria; Neyts, Johan; van Kuppeveld, Frank J M

    2015-01-01

    The genus Enterovirus of the family Picornaviridae contains many important human pathogens (e.g., poliovirus, coxsackievirus, rhinovirus, and enterovirus 71) for which no antiviral drugs are available. The viral RNA-dependent RNA polymerase is an attractive target for antiviral therapy.

  16. Potent antiviral flavone glycosides from Ficus benjamina leaves.

    Science.gov (United States)

    Yarmolinsky, Ludmila; Huleihel, Mahmoud; Zaccai, Michele; Ben-Shabat, Shimon

    2012-03-01

    Crude ethanol extracts from Ficus benjamina leaves strongly inhibit Herpes Simplex Virus 1 and 2 (HSV-1/2) as well as Varicella Zoster Virus (VZV) cell infection in vitro. Bioassay-guided fractionation of the crude extract demonstrated that the most efficient inhibition of HSV-1 and HSV-2 was obtained with the flavonoid fraction. The present study was aimed to further isolate, purify and identify substances with potent antiviral activity from the flavonoid fraction of F. benjamina extracts. Flavonoids were collected from the leaf ethanol extracts through repeated purification procedure and HPLC analysis. The antiviral activity of each substance was then evaluated in cell culture. Three known flavone glycosides, (1) quercetin 3-O-rutinoside, (2) kaempferol 3-O-rutinoside and (3) kaempferol 3-O-robinobioside, showing highest antiviral efficiency were selected and their structure was determined by spectroscopic analyses including NMR and mass spectrometry (MS). These three flavones were highly effective against HSV-1 reaching a selectivity index (SI) of 266, 100 and 666 for compound 1, 2 and 3, respectively, while the SI of their aglycons, quercetin and kaempferol amounted only in 7.1 and 3.2, respectively. Kaempferol 3-O-robinobioside showed similar SI to that of acyclovir (ACV), the standard anti-HSV drug. Although highly effective against HSV-1 and HSV-2, these flavone glycosides did not show any significant activity against VZV. Copyright © 2011 Elsevier B.V. All rights reserved.

  17. Using the ferret as an animal model for investigating influenza antiviral effectiveness

    Directory of Open Access Journals (Sweden)

    Ding Yuan Oh

    2016-02-01

    Full Text Available The concern of the emergence of a pandemic influenza virus has sparked an increased effort towards the development and testing of novel influenza antivirals. Central to this is the animal model of influenza infection, which has played an important role in understanding treatment effectiveness and the effect of antivirals on host immune responses. Among the different animal models of influenza, ferrets can be considered the most suitable for antiviral studies as they display most of the human-like symptoms following influenza infections, they can be infected with human influenza virus without prior viral adaptation and have the ability to transmit influenza virus efficiently between one another. However, an accurate assessment of the effectiveness of an antiviral treatment in ferrets is dependent on three major experimental considerations encompassing firstly, the volume and titre of virus, and the route of viral inoculation. Secondly, the route and dose of drug administration, and lastly, the different methods used to assess clinical symptoms, viral shedding kinetics and host immune responses in the ferrets. A good understanding of these areas is necessary to achieve data that can accurately inform the human use of influenza antivirals. In this review, we discuss the current progress and the challenges faced in these three major areas when using the ferret model to measure influenza antiviral effectiveness.

  18. Strategies for antiviral stockpiling for future influenza pandemics: a global epidemic-economic perspective.

    Science.gov (United States)

    Carrasco, Luis R; Lee, Vernon J; Chen, Mark I; Matchar, David B; Thompson, James P; Cook, Alex R

    2011-09-07

    Influenza pandemics present a global threat owing to their potential mortality and substantial economic impacts. Stockpiling antiviral drugs to manage a pandemic is an effective strategy to offset their negative impacts; however, little is known about the long-term optimal size of the stockpile under uncertainty and the characteristics of different countries. Using an epidemic-economic model we studied the effect on total mortality and costs of antiviral stockpile sizes for Brazil, China, Guatemala, India, Indonesia, New Zealand, Singapore, the UK, the USA and Zimbabwe. In the model, antivirals stockpiling considerably reduced mortality. There was greater potential avoidance of expected costs in the higher resourced countries (e.g. from $55 billion to $27 billion over a 30 year time horizon for the USA) and large avoidance of fatalities in those less resourced (e.g. from 11.4 to 2.3 million in Indonesia). Under perfect allocation, higher resourced countries should aim to store antiviral stockpiles able to cover at least 15 per cent of their population, rising to 25 per cent with 30 per cent misallocation, to minimize fatalities and economic costs. Stockpiling is estimated not to be cost-effective for two-thirds of the world's population under current antivirals pricing. Lower prices and international cooperation are necessary to make the life-saving potential of antivirals cost-effective in resource-limited countries.

  19. Strategies for antiviral stockpiling for future influenza pandemics: a global epidemic-economic perspective

    Science.gov (United States)

    Carrasco, Luis R.; Lee, Vernon J.; Chen, Mark I.; Matchar, David B.; Thompson, James P.; Cook, Alex R.

    2011-01-01

    Influenza pandemics present a global threat owing to their potential mortality and substantial economic impacts. Stockpiling antiviral drugs to manage a pandemic is an effective strategy to offset their negative impacts; however, little is known about the long-term optimal size of the stockpile under uncertainty and the characteristics of different countries. Using an epidemic–economic model we studied the effect on total mortality and costs of antiviral stockpile sizes for Brazil, China, Guatemala, India, Indonesia, New Zealand, Singapore, the UK, the USA and Zimbabwe. In the model, antivirals stockpiling considerably reduced mortality. There was greater potential avoidance of expected costs in the higher resourced countries (e.g. from $55 billion to $27 billion over a 30 year time horizon for the USA) and large avoidance of fatalities in those less resourced (e.g. from 11.4 to 2.3 million in Indonesia). Under perfect allocation, higher resourced countries should aim to store antiviral stockpiles able to cover at least 15 per cent of their population, rising to 25 per cent with 30 per cent misallocation, to minimize fatalities and economic costs. Stockpiling is estimated not to be cost-effective for two-thirds of the world's population under current antivirals pricing. Lower prices and international cooperation are necessary to make the life-saving potential of antivirals cost-effective in resource-limited countries. PMID:21296791

  20. Viral respiratory diseases: vaccines and antivirals.

    Science.gov (United States)

    Lennette, E H

    1981-01-01

    Acute respiratory diseases, most of which are generally attributed to viruses, account for about 6% of all deaths and for about 60% of the deaths associated with all respiratory disease. The huge cost attributable to viral respiratory infections as a result of absenteeism and the disruption of business and the burden of medical care makes control of these diseases an important objective. The viruses that infect the respiratory tract fall taxonomically into five viral families. Although immunoprophylaxis would appear to be the logical approach, the development of suitable vaccines has been confronted with numerous obstacles, including antigenic drift and shift in the influenzaviruses, the large number of antigenically distinct immunotypes among rhinoviruses, the occurrence after immunization of rare cases of a severe form of the disease following subsequent natural infection with respiratory syncytial virus, and the risk of oncogenicity of adenoviruses for man. Considerable expenditure on the development of new antiviral drugs has so far resulted in only three compounds that are at present officially approved and licensed for use in the USA. Efforts to improve the tools available for control should continue and imaginative and inventive approaches are called for. However, creativity and ingenuity must operate within the constraints imposed by economic, political, ethical, and legal considerations.

  1. Antiviral active peptide from oyster

    Science.gov (United States)

    Zeng, Mingyong; Cui, Wenxuan; Zhao, Yuanhui; Liu, Zunying; Dong, Shiyuan; Guo, Yao

    2008-08-01

    An active peptide against herpes virus was isolated from the enzymic hydrolysate of oyster ( Crassostrea gigas) and purified with the definite direction hydrolysis technique in the order of alcalase and bromelin. The hydrolysate was fractioned into four ranges of molecular weight (>10 kDa, 10 5 kDa, 5 1 kDa and <1 kDa) using ultrafiltration membranes and dialysis. The fraction of 10 5 kDa was purified using consecutive chromatographic methods including DEAE Sephadex A-25 column, Sephadex G-25 column, and high performance liquid chromatogram (HPLC) by activity-guided isolation. The antiviral effect of the obtained peptide on herpetic virus was investigated in Vero cells by observing cytopathic effect (CPE). The result shows that the peptide has high inhibitory activity on herpetic virus.

  2. Antiviral Perspectives for Chikungunya Virus

    Directory of Open Access Journals (Sweden)

    Deepti Parashar

    2014-01-01

    Full Text Available Chikungunya virus (CHIKV is a mosquito-borne pathogen that has a major health impact in humans and causes acute febrile illness in humans accompanied by joint pains and, in many cases, persistent arthralgia lasting for weeks to years. CHIKV reemerged in 2005-2006 in several parts of the Indian Ocean islands and India after a gap of 32 years, causing millions of cases. The re-emergence of CHIKV has also resulted in numerous outbreaks in several countries in the eastern hemisphere, with a threat to further expand in the near future. However, there is no vaccine against CHIKV infection licensed for human use, and therapy for CHIKV infection is still mainly limited to supportive care as antiviral agents are yet in different stages of testing or development. In this review we explore the different perspectives for chikungunya treatment and the effectiveness of these treatment regimens and discuss the scope for future directions.

  3. Drug: D06512 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D06512 Drug Freeze-dried live attenuated rubella vaccine (JP17) ... Antiviral ... DG01689 ... Live vaccine... ... DG01687 ... Parenteral live vaccine Therapeutic category: 6313 ATC code: J07BJ01 ... PubChem: 47208168 ...

  4. Drug: D10214 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10214 Drug Adsorbed diphtheria-purified pertussis-tetanus-inactivated polio combined vaccine...; Quattrovac (TN); Tetrabik (TN) ... Antiviral ... DG01686 ... Inactivated vaccine Therapeutic category: 6361 ... PubChem: 163312245 ...

  5. Drug: D08776 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08776 Drug Pneumococcus vaccine; Pneumococcal vaccine; Pneumovax 23 (TN) ... An...tiviral ... DG01686 ... Inactivated vaccine Therapeutic category: 6311 ATC code: J07AL01 ... PubChem: 96025459 ...

  6. Drug: D05544 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D05544 Drug Live oral polimyelitis vaccine (JP17); Poliovirus vaccine live oral; O...rimune (TN) ... Antiviral ... DG01689 ... Live vaccine ... DG01688 ... Oral live vaccine ATC code: J07BF01 ... PubChem: 17398306 ...

  7. Drug: D05356 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D05356 Drug Adsorbed diphtheria-purified pertussis-tetanus combined vaccine (JP17)... ... Antiviral ... DG01686 ... Inactivated vaccine Therapeutic category: 6361 ... PubChem: 17398290 ...

  8. Drug: D10213 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10213 Drug Pneumococcal polysaccharide conjugate vaccine (adsorbed); Prevenar (TN...) ... Antiviral ... DG01686 ... Inactivated vaccine ATC code: J07AL02 Chemical group: DG00672 ... PubChem: 163312244 ...

  9. Drug: D10455 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10455 Drug Pneumococcal 13-valent conjugate vaccine; Prevenar 13 (TN) ... Antiv...iral ... DG01686 ... Inactivated vaccine Therapeutic category: 6311 ATC code: J07AL02 Chemical group: DG00672 ... PubChem: 172232548 ...

  10. Drug: D04536 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D04536 Drug Influenza virus vaccine (USP); FluShield (TN); Fluarix quadrivalent (T...N) ... Antiviral ... DG01686 ... Inactivated vaccine ATC code: J07BB01 Chemical group: DG00674 ... PubChem: 47206383 ...

  11. Drug: D10212 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10212 Drug Recombinant adsorbed bivalent human papillomavirus-like particle vaccine... (derived from Trichoplusia ni cells); Cervarix (TN) ... Antiviral ... DG01686 ... Inactivated vaccine Therapeutic category: 6313 ATC code: J07BM02 ... PubChem: 163312243 ...

  12. Drug: D10192 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10192 Drug Recombinant adsorbed quadrivalent human papillomavirus virus-like particle vaccine... (yeast origin); Gardasil (TN); Silgard (TN) ... Antiviral ... DG01686 ... Inactivated vaccine Therapeutic category: 6313 ATC code: J07BM01 ... PubChem: 135626910 ...

  13. Drug: D04866 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D04866 Drug Freeze-dried live attenuated measles vaccine (JP17) ... Antiviral ... DG01689 ... Live vaccine... ... DG01687 ... Parenteral live vaccine Therapeutic category: 6313 ATC code: J07BD01 ... PubChem: 17398201 ...

  14. Drug: D05313 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D05313 Drug Japanese encephalitis vaccine (JP17); Freeze-dried japanese encephalitis vaccine... (JP17); Ixiaro (TN) ... Antiviral ... DG01686 ... Inactivated vaccine Therapeutic category: 6313 ATC code: J07BA02 ... PubChem: 17398274 ...

  15. Drug: D03063 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D03063 Drug BCG vaccine (USP); Tice BCG (TN) ... Antiviral ... DG01689 ... Live vaccine... ... DG01687 ... Parenteral live vaccine ATC code: L03AX03 Chemical group: DG00738 ... PubChem: 17397218 ...

  16. Antiviral therapy and prophylaxis of acute respiratory infections

    Directory of Open Access Journals (Sweden)

    L. V. Osidak

    2012-01-01

    Full Text Available Thearticle presents the results of years of studies (including biochemical and immunological of the effectiveness of application and prophylaxis (in relation to nosocomial infections and the safety of antiviral chemical preparation Arbidol in 694 children with influenza and influenza-like illness, including the coronavirus infection (43 children and combined lesions of respiratory tract (150, indicating the possible inclusion of the drug in the complex therapy for children with the listed diseases, regardless of the severity and nature of their course. The studies were conducted according to the regulated standard of test conditions and randomized clinical trials.

  17. Cytotoxic, virucidal, and antiviral activity of South American plant and algae extracts.

    Science.gov (United States)

    Faral-Tello, Paula; Mirazo, Santiago; Dutra, Carmelo; Pérez, Andrés; Geis-Asteggiante, Lucía; Frabasile, Sandra; Koncke, Elina; Davyt, Danilo; Cavallaro, Lucía; Heinzen, Horacio; Arbiza, Juan

    2012-01-01

    Herpes simplex virus type 1 (HSV-1) infection has a prevalence of 70% in the human population. Treatment is based on acyclovir, valacyclovir, and foscarnet, three drugs that share the same mechanism of action and of which resistant strains have been isolated from patients. In this aspect, innovative drug therapies are required. Natural products offer unlimited opportunities for the discovery of antiviral compounds. In this study, 28 extracts corresponding to 24 plant species and 4 alga species were assayed in vitro to detect antiviral activity against HSV-1. Six of the methanolic extracts inactivated viral particles by direct interaction and 14 presented antiviral activity when incubated with cells already infected. Most interesting antiviral activity values obtained are those of Limonium brasiliense, Psidium guajava, and Phyllanthus niruri, which inhibit HSV-1 replication in vitro with 50% effective concentration (EC(50)) values of 185, 118, and 60 μg/mL, respectively. For these extracts toxicity values were calculated and therefore selectivity indexes (SI) obtained. Further characterization of the bioactive components of antiviral plants will pave the way for the discovery of new compounds against HSV-1.

  18. Cytotoxic, Virucidal, and Antiviral Activity of South American Plant and Algae Extracts

    Directory of Open Access Journals (Sweden)

    Paula Faral-Tello

    2012-01-01

    Full Text Available Herpes simplex virus type 1 (HSV-1 infection has a prevalence of 70% in the human population. Treatment is based on acyclovir, valacyclovir, and foscarnet, three drugs that share the same mechanism of action and of which resistant strains have been isolated from patients. In this aspect, innovative drug therapies are required. Natural products offer unlimited opportunities for the discovery of antiviral compounds. In this study, 28 extracts corresponding to 24 plant species and 4 alga species were assayed in vitro to detect antiviral activity against HSV-1. Six of the methanolic extracts inactivated viral particles by direct interaction and 14 presented antiviral activity when incubated with cells already infected. Most interesting antiviral activity values obtained are those of Limonium brasiliense, Psidium guajava, and Phyllanthus niruri, which inhibit HSV-1 replication in vitro with 50% effective concentration (EC50 values of 185, 118, and 60 μg/mL, respectively. For these extracts toxicity values were calculated and therefore selectivity indexes (SI obtained. Further characterization of the bioactive components of antiviral plants will pave the way for the discovery of new compounds against HSV-1.

  19. Potential of small-molecule fungal metabolites in antiviral chemotherapy.

    Science.gov (United States)

    Roy, Biswajit G

    2017-08-01

    Various viral diseases, such as acquired immunodeficiency syndrome, influenza, and hepatitis, have emerged as leading causes of human death worldwide. Scientific endeavor since invention of DNA-dependent RNA polymerase of pox virus in 1967 resulted in better understanding of virus replication and development of various novel therapeutic strategies. Despite considerable advancement in every facet of drug discovery process, development of commercially viable, safe, and effective drugs for these viruses still remains a big challenge. Decades of intense research yielded a handful of natural and synthetic therapeutic options. But emergence of new viruses and drug-resistant viral strains had made new drug development process a never-ending battle. Small-molecule fungal metabolites due to their vast diversity, stereochemical complexity, and preapproved biocompatibility always remain an attractive source for new drug discovery. Though, exploration of therapeutic importance of fungal metabolites has started early with discovery of penicillin, recent prediction asserted that only a small percentage (5-10%) of fungal species have been identified and much less have been scientifically investigated. Therefore, exploration of new fungal metabolites, their bioassay, and subsequent mechanistic study bears huge importance in new drug discovery endeavors. Though no fungal metabolites so far approved for antiviral treatment, many of these exhibited high potential against various viral diseases. This review comprehensively discussed about antiviral activities of fungal metabolites of diverse origin against some important viral diseases. This also highlighted the mechanistic details of inhibition of viral replication along with structure-activity relationship of some common and important classes of fungal metabolites.

  20. Transdermal Delivery and Cutaneous Targeting of Antivirals using a Penetration Enhancer and Lysolipid Prodrugs

    Czech Academy of Sciences Publication Activity Database

    Diblíková, D.; Kopečná, M.; Školová, B.; Krečmerová, Marcela; Roh, J.; Hrabálek, A.; Vávrová, K.

    2014-01-01

    Roč. 31, č. 4 (2014), s. 1071-1081 ISSN 0724-8741 Grant - others:GA ČR(CZ) GAP207/11/0365 Institutional support: RVO:61388963 Keywords : acyclic nucleoside phosphonate antivirals * lysolipid prodrug * penetration enhancer * skin absorption * transdermal drug delivery Subject RIV: FR - Pharmacology ; Medidal Chemistry Impact factor: 3.420, year: 2014

  1. Antiviral activity of Dianthus superbusn L. against hepatitis B virus in ...

    African Journals Online (AJOL)

    Background: Hepatitis is a viral infection of hepatitis B virus (HBV). Limitations of drug used in the management of it opens the interest related to alternative medicine. The given study deals with the antiviral activity of Dianthus superbusn L. (DSL) against HBV in vitro & in vivo. Material and Methods: In vitro study liver cell line ...

  2. Viruses and Antiviral Immunity in Drosophila

    Science.gov (United States)

    Xu, Jie; Cherry, Sara

    2013-01-01

    Viral pathogens present many challenges to organisms, driving the evolution of a myriad of antiviral strategies to combat infections. A wide variety of viruses infect invertebrates, including both natural pathogens that are insect-restricted, and viruses that are transmitted to vertebrates. Studies using the powerful tools available in the model organism Drosophila have expanded our understanding of antiviral defenses against diverse viruses. In this review, we will cover three major areas. First, we will describe the tools used to study viruses in Drosophila. Second, we will survey the major viruses that have been studied in Drosophila. And lastly, we will discuss the well-characterized mechanisms that are active against these diverse pathogens, focusing on non-RNAi mediated antiviral mechanisms. Antiviral RNAi is discussed in another paper in this issue. PMID:23680639

  3. Developing Novel Antimicrobial and Antiviral Textile Products.

    Science.gov (United States)

    Iyigundogdu, Zeynep Ustaoglu; Demir, Okan; Asutay, Ayla Burcin; Sahin, Fikrettin

    2017-03-01

    In conjunction with an increasing public awareness of infectious diseases, the textile industry and scientists are developing hygienic fabrics by the addition of various antimicrobial and antiviral compounds. In the current study, sodium pentaborate pentahydrate and triclosan are applied to cotton fabrics in order to gain antimicrobial and antiviral properties for the first time. The antimicrobial activity of textiles treated with 3 % sodium pentaborate pentahydrate, 0.03 % triclosan, and 7 % Glucapon has been investigated against a broad range of microorganisms including bacteria, yeast, and fungi. Moreover, modified cotton fabrics were tested against adenovirus type 5 and poliovirus type 1. According to the test results, the modified textile goods attained very good antimicrobial and antiviral properties. Thus, the results of the present study clearly suggest that sodium pentaborate pentahydrate and triclosan solution-treated textiles can be considered in the development of antimicrobial and antiviral textile finishes.

  4. Surveillance of antiviral resistance markers in Argentina: detection of E119V neuraminidase mutation in a post-treatment immunocompromised patient

    Directory of Open Access Journals (Sweden)

    Andrea Pontoriero

    Full Text Available Although vaccines are the best means of protection against influenza, neuraminidase inhibitors are currently the main antiviral treatment available to control severe influenza cases. One of the most frequent substitutions in the neuraminidase (NA protein of influenza A(H3N2 viruses during or soon after oseltamivir administration is E119V mutation. We describe the emergence of a mixed viral population with the E119E/V mutation in the NA protein sequence in a post-treatment influenza sample collected from an immunocompromised patient in Argentina. This substitution was identified by a real-time reverse transcriptase polymerase chain reaction (RT-PCR protocol and was confirmed by direct Sanger sequencing of the original sample. In 2014, out of 1140 influenza samples received at the National Influenza Centre, 888 samples (78% were A(H3N2 strains, 244 (21.3% were type B strains, and 8 (0.7% were A(H1N1pdm09 strains. Out of 888 A(H3N2 samples, 842 were tested for the E119V substitution by quantitative RT-PCR: 841 A(H3N2 samples had the wild-type E119 genotype and in one sample, a mixture of viral E119/ V119 subpopulations was detected. Influenza virus surveillance and antiviral resistance studies can lead to better decisions in health policies and help in medical treatment planning, especially for severe cases and immunocompromised patients.

  5. Optimization of Influenza Antiviral Response in Texas

    Science.gov (United States)

    2015-03-01

    originated 38 from Texas- Mexico border counties, TAVRS would average the 150 treatable curves that apply to that influenza scenario to be used in... INFLUENZA ANTIVIRAL RESPONSE IN TEXAS by Travis L. Chambers March 2015 Advisor: Nedialko B. Dimitrov Co-Advisor: Michael Atkinson Second...DATES COVERED March 2015 Master ’s Thesis 4. TITLE AND SUBTITLE OPTIMIZATION OF INFLUENZA ANTIVIRAL RESPONSE IN TEXAS 6. AUTHOR(S) Travis L. Chambers

  6. Antiviral therapy of chronic hepatitis B.

    OpenAIRE

    Zoulim, Fabien

    2006-01-01

    Treatment of chronic hepatitis B remains a clinical challenge. Long-term viral suppression is a major goal of antiviral therapy to improve the clinical outcome of the patients. Antiviral treatment of chronic hepatitis B relies currently on immune modulators such as interferon alpha and its pegylated form, and viral polymerase inhibitors. Because of the slow kinetics of viral clearance and the spontaneous viral genome variability, viral mutants resistant to nucleoside analogs may be selected. ...

  7. Antiviral resistance in herpes simplex virus and varicella-zoster virus infections: diagnosis and management.

    Science.gov (United States)

    Piret, Jocelyne; Boivin, Guy

    2016-12-01

    Aciclovir (ACV) is the first-line drug for the management of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. Long-term administration of ACV for the treatment of severe infections in immunocompromised patients can lead to the development of drug resistance. Furthermore, the emergence of isolates resistant to ACV is increasingly recognized in immunocompetent individuals with herpetic keratitis. This review describes the mechanisms involved in drug resistance for HSV and VZV, the laboratory diagnosis and management of patients with infections refractory to ACV therapy. Genotypic testing is more frequently performed for the diagnosis of infections caused by drug-resistant HSV or VZV isolates. Molecular biology-based systems for the generation of recombinant viruses have been developed to link unknown mutations with their drug phenotypes. Fast and sensitive methods based on next-generation sequencing will improve the detection of heterogeneous viral populations of drug-resistant viruses and their temporal changes during antiviral therapy, which could allow better patient management. Novel promising compounds acting on targets that differ from the viral DNA polymerase are under clinical development. Antiviral drug resistance monitoring for HSV and VZV is required for a rational use of antiviral therapy in high-risk populations.

  8. Antiviral Therapy for Hepatitis C.

    Science.gov (United States)

    Lipman, Michelle M.; Cotler, Scott J.

    2003-12-01

    Current treatment for hepatitis C virus infection consists of pegylated interferon and ribavirin. The most important predictors of response to antiviral therapy for HCV include genotype 2 or 3 infection, baseline viral load less than 2 million copies/mL, and the absence of cirrhosis. Hepatitis C genotype and viral load should be obtained prior to initiating therapy. Liver biopsy can be used to stage the liver disease, to provide prognostic information, and to evaluate for coexisting causes of liver injury. Patients with genotype 1 infection require 48 weeks of therapy and a ribavirin dosage of 1000 to 1200 mg/d to achieve an optimal response. Patients with genotype 2 or 3 infection require only 24 weeks of treatment and a ribavirin dose of 800 mg/d. Treatment may be discontinued in patients who do not have a 100-fold reduction in hepatitis C virus RNA level from baseline at week 12 because they are unlikely to achieve a sustained response with further therapy. Patients with cirrhosis and hepatic decompensation or a small hepatocellular carcinoma should be evaluated for liver transplantation.

  9. Antiviral Activity of Natural Products Extracted from Marine Organisms

    Directory of Open Access Journals (Sweden)

    Sobia Tabassum

    2011-11-01

    Full Text Available Many epidemics have broken out over the centuries. Hundreds and thousands of humans have died over a disease. Available treatments for infectious diseases have always been limited. Some infections are more deadly than the others, especially viral pathogens. These pathogens have continuously resisted all kinds of medical treatment, due to a need for new treatments to be developed. Drugs are present in nature and are also synthesized in vitro and they help in combating diseases and restoring health. Synthesizing drugs is a hard and time consuming task, which requires a lot of man power and financial aid. However, the natural compounds are just lying around on the earth, may it be land or water. Over a thousand novel compounds isolated from marine organisms are used as antiviral agents. Others are being pharmacologically tested. Today, over forty antiviral compounds are present in the pharmacological market. Some of these compounds are undergoing clinical and pre-clinical stages. Marine compounds are paving the way for a new trend in modern medicine.

  10. In-vitro antiviral efficacy of ribavirin and interferon-alpha against canine distemper virus.

    Science.gov (United States)

    Carvalho, Otávio V; Saraiva, Giuliana L; Ferreira, Caroline G T; Felix, Daniele M; Fietto, Juliana L R; Bressan, Gustavo C; Almeida, Márcia R; Silva Júnior, Abelardo

    2014-10-01

    Canine distemper is a highly contagious disease with high incidence and lethality in the canine population. The objective of this study was to evaluate the efficacy of antiviral action with ribavirin (RBV), interferon-alpha (IFNα), and combinations of RBV and IFNα against canine distemper virus (CDV). Vero cells inoculated with CDV were treated with RBV, IFNα, and combinations of these drugs. The efficacy to inhibit viral replication was evaluated by adding the compounds at different times to determine which step of the viral replicative process was affected. Both drugs were effective against CDV in vitro. The IFNα was the most active compound, with an average IC50 (50% inhibitory concentration) value lower than the IC50 of the RBV. Ribavirin (RBV) was more selective than IFNα, however, and neither drug showed extracellular antiviral activity. The combination of RBV and IFNα exhibited antiviral activity for the intra- and extracellular stages of the replicative cycle of CDV, although the intracellular viral inhibition was higher. Both RBV and IFNα showed high antiviral efficacy against CDV, and furthermore, RBV + IFNα combinations have shown greater interference range in viral infectivity. These compounds could potentially be used to treat clinical disease associated with CDV infection.

  11. Viral Response to Specifically Targeted Antiviral Therapy for Hepatitis C and the Implications for Treatment Success

    Directory of Open Access Journals (Sweden)

    Curtis L Cooper

    2010-01-01

    Full Text Available Currently, hepatitis C virus (HCV antiviral therapy is characterized by long duration, a multitude of side effects, difficult administration and suboptimal success; clearly, alternatives are needed. Collectively, specifically targeted antiviral therapy for HCV (STAT-C molecules achieve rapid viral suppression and very high rapid virological response rates, and improve sustained virological response rates. The attrition rate of agents within this class has been high due to various toxicities. Regardless, several STAT-C molecules are poised to become the standard of care for HCV treatment in the foreseeable future. Optimism must be tempered with concerns related to the rapid development of drug resistance with resulting HCV rebound. Strategies including induction dosing with interferon and ribavirin, use of combination high-potency STAT-C molecules and an intensive emphasis on adherence to HCV antiviral therapy will be critical to the success of this promising advance in HCV therapy.

  12. Nucleoside Phosphate-Conjugates Come of Age: Catalytic Transformation, Polymerase Recognition and Antiviral Properties.

    Science.gov (United States)

    Groaz, Elisabetta; Herdewijn, Piet

    2015-01-01

    Over the past few decades, different types of nucleoside phosphate-conjugates have been under extensive investigation due to their favorable molecular lability with interesting catalytic hydrolysis mechanisms, recognition as polymerase substrates, and especially for their development as antiviral/ anticancer protide therapeutics. The antiviral conjugates such as nucleoside phosphoesters and phosphoramidates that were discovered and developed in the initial years have been well reviewed by the pioneers in the field. In the present review, we will discuss the basic chemical and biological principles behind consideration of some representative structural classes. We will also summarize the chemical and biological properties of some of the more recent analogues that were synthesized and evaluated in our laboratory and by others. This includes new principles for their application as direct substrates of polymerases, nucleobasedependent catalytic and antiviral activity, and a plausible 'prodrug of a prodrug' strategy for tissue/organ-specific targeted drug delivery.

  13. Direct-acting antiviral agents for hepatitis C virus infection.

    Science.gov (United States)

    Kiser, Jennifer J; Flexner, Charles

    2013-01-01

    Two selective inhibitors of the hepatitis C virus (HCV) protease nearly double the cure rates for this infection when combined with peginterferon alfa and ribavirin. These drugs, boceprevir and telaprevir, received regulatory approval in 2011 and are the first direct-acting antiviral agents (DAAs) that selectively target HCV. During 2012, at least 30 additional DAAs were in various stages of clinical development. HCV protease inhibitors, polymerase inhibitors, and NS5A inhibitors (among others) can achieve high cure rates when combined with peginterferon alfa and ribavirin and demonstrate promise when used in combination with one another. Current research is attempting to improve the pharmacokinetics and tolerability of these agents, define the best regimens, and determine treatment strategies that produce the best outcomes. Several DAAs will reach the market simultaneously, and resources will be needed to guide the use of these drugs. We review the clinical pharmacology, trial results, and remaining challenges of DAAs for the treatment of HCV.

  14. Antiviral activity of Acacia nilotica against Hepatitis C Virus in liver infected cells

    Directory of Open Access Journals (Sweden)

    Javed Tariq

    2011-05-01

    Full Text Available Abstract Hepatitis C virus (HCV belonging to the family Flaviviridae has infected 3% of the population worldwide and 6% of the population in Pakistan. The only recommended standard treatment is pegylated INF-α plus ribavirin. Due to less compatibility of the standard treatment, thirteen medicinal plants were collected from different areas of Pakistan on the basis of undocumented antiviral reports against different viral infections. Medicinal plants were air dried, extracted and screened out against HCV by infecting HCV inoculums of 3a genotype in liver cells. RT-PCR results demonstrate that acetonic and methanolic extract of Acacia nilotica (AN showed more than 50% reduction at non toxic concentration. From the above results, it can be concluded that by selecting different molecular targets, specific structure-activity relationship can be achieved by doing mechanistic analysis. So, additional studies are required for the isolation and recognition of antiviral compound in AN to establish its importance as antiviral drug against HCV. For further research, we will scrutinize the synergistic effect of active antiviral compound in combination with standard PEG INF-α and ribavirin which may be helpful in exploring further gateways for antiviral therapy against HCV.

  15. A Review of the Antiviral Properties of Black Elder (Sambucus nigra L.) Products.

    Science.gov (United States)

    Porter, Randall S; Bode, Robert F

    2017-04-01

    Black elder (Sambucus nigra L.) has a long ethnobotanical history across many disparate cultures as a treatment for viral infection and is currently one of the most-used medicinal plants worldwide. Until recently, however, substantial scientific research concerning its antiviral properties has been lacking. Here, we evaluate the state of current scientific research concerning the use of elderberry extract and related products as antivirals, particularly in the treatment of influenza, as well as their safety and health impacts as dietary supplements. While the extent of black elder's antiviral effects are not well known, antiviral and antimicrobial properties have been demonstrated in these extracts, and the safety of black elder is reflected by the United States Food and Drug Administration approval as generally recognized as safe. A deficit of studies comparing these S. nigra products and standard antiviral medications makes informed and detailed recommendations for use of S. nigra extracts in medical applications currently impractical. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  16. Antiviral therapy with nucleotide/nucleoside analogues in chronic hepatitis B: A meta-analysis of prospective randomized trials.

    Science.gov (United States)

    Bedre, Renesh H; Raj, Utkarsh; Misra, Sri Prakash; Varadwaj, Pritish Kumar

    2016-03-01

    Nucleotide/nucleoside analogues (antiviral therapy) are used in the therapy of HBeAg positive and HBeAg negative chronic hepatitis B. We analyzed ten selected randomized controlled with 2557 patients to estimate the effect of antiviral drugs in chronic hepatitis B with compared to placebo. Virological response, biochemical response, histological response, seroconversion of HBeAg, and loss of HBeAg were estimated as primary efficacy measures. The included studies were subjected for heterogeneity and publication bias. The heterogeneity was assessed with χ2 and I(2) statistics. Publication bias was assessed by funnel plot. Greater rates of improvement obtained in antiviral group for virological response [43.96 % vs. 3.15 %, RR = 0.57, 95 % CI = 0.54-0.61, p-value Antiviral therapy provided significant benefit for the treatment of chronic hepatitis B with no measurable adverse effects.

  17. Hepatitis B virus reactivation after withdrawal of prophylactic antiviral therapy in patients with diffuse large B cell lymphoma.

    Science.gov (United States)

    Liu, Wei Ping; Wang, Xiao Pei; Zheng, Wen; Ping, Ling Yan; Zhang, Chen; Wang, Gui Qiang; Song, Yu Qin; Zhu, Jun

    2016-01-01

    The exact incidence and severity of hepatitis B virus (HBV) reactivation after the withdrawal of prophylactic antiviral therapy (delayed HBV reactivation) is unknown. We retrospectively analyzed 107 newly diagnosed diffuse large B cell lymphoma patients with HBV infection who received chemotherapy. The median time from the cessation of antitumor therapy to the withdrawal of prophylactic antiviral therapy was 6.1 months. The incidence of delayed HBV reactivation was 21.7% in HBsAg-positive group and 0 in HBsAg-negative/anti-HBc-positive group (P 8 cycles) were independent risk factors of HBV reactivation in HBsAg-positive patients. In conclusion, prophylactic antiviral therapy could be withdrawn 6 months after the cessation of chemotherapy in HBsAg-negative/anti-HBc-positive patients. However, a longer course of prophylactic antiviral drug administration may be an optimal option to prevent delayed HBV reactivation for HBsAg-positive patients.

  18. Surveillance of Oseltamivir-Resistant Influenza A(H1N1)pdm09 in Guanajuato State, Mexico from 2009 to 2012.

    Science.gov (United States)

    Mosqueda-Gómez, Juan Luis; Belaunzarán-Zamudio, Pablo Francisco; Barba, Adriana; Córdova-Villalobos, José A; Cuellar-Rodríguez, Jennifer Margarita; Ernesto Macías, Alejandro

    2015-01-01

    The influenza A(H1N1)pdm09 virus was first identified in Mexico in April 2009, subsequently spreading worldwide. Soon after the WHO declared a pandemic, a series of cases involving oseltamivir-resistant viruses were described, following concerns about the spread of strains resistant to neuraminidase inhibitors that could hamper control measures. To study the prevalence of oseltamivir-resistant influenza A(H1N1)pdm09, we implemented a surveillance program across the state of Guanajuato, Mexico. We collected respiratory samples from patients with confirmed infection with influenza A(H1N1)pdm09 virus between 2009 and 2012 in rural and urban regions in Guanajuato, Mexico. Specimens were screened for the H275Y mutation by Sanger sequencing. A total of 1,192 laboratory confirmed influenza A(H1N1)pdm09-positive samples were processed between 2009 and 2012. Using two endpoint real-time polymerase chain reaction, 575 samples were sequenced. Two different clusters, I and II, were identified. The H275Y substitution was found in only one sample from cluster I. The prevalence of oseltamivir-resistant influenza A(H1N1)pdm09 2009 viruses during the pandemic period and following years was very low in our State.

  19. GRL-09510, a Unique P2-Crown-Tetrahydrofuranylurethane -Containing HIV-1 Protease Inhibitor, Maintains Its Favorable Antiviral Activity against Highly-Drug-Resistant HIV-1 Variants in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Amano, Masayuki; Miguel Salcedo-Gómez, Pedro; Yedidi, Ravikiran S.; Delino, Nicole S.; Nakata, Hirotomo; Venkateswara Rao, Kalapala; Ghosh, Arun K.; Mitsuya, Hiroaki

    2017-09-25

    We report that GRL-09510, a novel HIV-1 protease inhibitor (PI) containing a newly-generated P2-crown-tetrahydrofuranylurethane (Crwn-THF), a P2'-methoxybenzene, and a sulfonamide isostere, is highly active against laboratory and primary clinical HIV-1 isolates (EC50: 0.0014–0.0028 μM) with minimal cytotoxicity (CC50: 39.0 μM). Similarly, GRL-09510 efficiently blocked the replication of HIV-1NL4-3 variants, which were capable of propagating at high-concentrations of atazanavir, lopinavir, and amprenavir (APV). GRL-09510 was also potent against multi-drug-resistant clinical HIV-1 variants and HIV-2ROD. Under the selection condition, where HIV-1NL4-3 rapidly acquired significant resistance to APV, an integrase inhibitor raltegravir, and a GRL-09510 congener (GRL-09610), no variants highly resistant against GRL-09510 emerged over long-term in vitro passage of the virus. Crystallographic analysis demonstrated that the Crwn-THF moiety of GRL-09510 forms strong hydrogen-bond-interactions with HIV-1 protease (PR) active-site amino acids and is bulkier with a larger contact surface, making greater van der Waals contacts with PR than the bis-THF moiety of darunavir. The present data demonstrate that GRL-09510 has favorable features for treating patients infected with wild-type and/or multi-drug-resistant HIV-1 variants, that the newly generated P2-Crwn-THF moiety confers highly desirable anti-HIV-1 potency. The use of the novel Crwn-THF moiety sheds lights in the design of novel PIs.

  20. Hedging against antiviral resistance during the next influenza pandemic using small stockpiles of an alternative chemotherapy.

    Directory of Open Access Journals (Sweden)

    Joseph T Wu

    2009-05-01

    Full Text Available The effectiveness of single-drug antiviral interventions to reduce morbidity and mortality during the next influenza pandemic will be substantially weakened if transmissible strains emerge which are resistant to the stockpiled antiviral drugs. We developed a mathematical model to test the hypothesis that a small stockpile of a secondary antiviral drug could be used to mitigate the adverse consequences of the emergence of resistant strains.We used a multistrain stochastic transmission model of influenza to show that the spread of antiviral resistance can be significantly reduced by deploying a small stockpile (1% population coverage of a secondary drug during the early phase of local epidemics. We considered two strategies for the use of the secondary stockpile: early combination chemotherapy (ECC; individuals are treated with both drugs in combination while both are available; and sequential multidrug chemotherapy (SMC; individuals are treated only with the secondary drug until it is exhausted, then treated with the primary drug. We investigated all potentially important regions of unknown parameter space and found that both ECC and SMC reduced the cumulative attack rate (AR and the resistant attack rate (RAR unless the probability of emergence of resistance to the primary drug p(A was so low (less than 1 in 10,000 that resistance was unlikely to be a problem or so high (more than 1 in 20 that resistance emerged as soon as primary drug monotherapy began. For example, when the basic reproductive number was 1.8 and 40% of symptomatic individuals were treated with antivirals, AR and RAR were 67% and 38% under monotherapy if p(A = 0.01. If the probability of resistance emergence for the secondary drug was also 0.01, then SMC reduced AR and RAR to 57% and 2%. The effectiveness of ECC was similar if combination chemotherapy reduced the probabilities of resistance emergence by at least ten times. We extended our model using travel data between 105

  1. T-705 (Favipiravir) suppresses tumor necrosis factor α production in response to influenza virus infection: A beneficial feature of T-705 as an anti-influenza drug.

    Science.gov (United States)

    Tanaka, T; Kamiyama, T; Daikoku, T; Takahashi, K; Nomura, N; Kurokawa, M; Shiraki, K

    Influenza virus infection induces the production of various cytokines, which play important roles in the pathogenesis of infection. Among the cytokines induced by influenza, tumor necrosis factor α (TNF-α) production has been correlated with the severity of lung lesions. We investigated the effects of T-705 (Favipiravir, 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) on cytokine production due to influenza virus infection in vitro and in vivo, compared with oseltamivir or GS 4071, an active form of oseltamivir. TNF-α production in mouse macrophage-derived P388D1 cells infected with the influenza virus was lower following treatment with T-705 at concentrations of 0.3 to 100 µg/ml than treatment with GS 4071 at the same concentrations. The effect of treatment with T-705 on the cytokine production induced by the influenza virus infection was investigated in mouse influenza virus infection model. At 48 h post-infection (p.i.) T-705 significantly suppressed the viral load in the lungs and TNF-α production in the airways of infected mice even when viral loads were high. Furthermore, T-705 suppressed only TNF-α production from the early phase of infection. In this study, T-705 showed the antiviral activity of reducing pulmonary viral load compared with oseltamivir, thereby suppressing the TNF-α production. This feature of T-705 is benefit against severe influenza infection.

  2. NaVirCept - Nucleic Acid-Based Anti-Viral Project

    International Nuclear Information System (INIS)

    Stephen, E. R.; Wong, J.; Van Loon, D.

    2007-01-01

    Vaccines are generally considered to be the most effective countermeasures to bacterial and viral diseases, however, licensed vaccines against many disease agents are either not available or their efficacies have not been demonstrated. Vaccines are generally agent specific in terms of treatment spectrum and are subject to defeat through natural mutation or through directed efforts. With respect to viral therapeutics, one of the major limitations associated with antiviral drugs is acquired drug resistance caused by antigenic shift or drift. A number of next-generation prophylactic and/or therapeutic measures are on the horizon. Of these, nucleic acid-based drugs are showing great antiviral potential. These drugs elicit long-lasting, broad spectrum protective immune responses, especially to respiratory viral pathogens. The Nucleic Acid-Based Antiviral (NaVirCept) project provides the opportunity to demonstrate the effectiveness of novel medical countermeasures against military-significant endemic and other viral threat agents. This project expands existing DRDC drug delivery capability development, in the form of proprietary liposome intellectual property, by coupling it with leading-edge nucleic acid-based technology to deliver effective medical countermeasures that will protect deployed personnel and the warfighter against a spectrum of viral disease agents. The technology pathway will offer a means to combat emerging viral diseases or modified threat agents such as the bird flu or reconstructed Spanish flu without going down the laborious, time-consuming and expensive paths to develop countermeasures for each new and/or emerging viral disease organism.(author)

  3. Use of tissue culture cell lines to evaluate HIV antiviral resistance.

    Science.gov (United States)

    Krowicka, Halina; Robinson, James E; Clark, Rebecca; Hager, Shannon; Broyles, Stephanie; Pincus, Seth H

    2008-07-01

    Most current assays of HIV antiviral resistance are based on either sequencing of viral genes (genotypic assays) or amplification and insertion of these genes into standardized virus backbones and culture. These latter are called phenotypic assays. But the only generally accepted phenotypic assay is based upon culture of intact patient virus, performed in phytohemagglutinin-activated peripheral blood mononuclear cells (PHA blasts) in the presence of differing drug concentrations. However, PHA blast culture is difficult and not always reproducible. Therefore we have sought cell lines that may produce more predictable results, yet faithfully mirror results in PHA blasts. We have compared 10 different cell lines for receptor and coreceptor expression, growth of laboratory-adapted strains of HIV, growth by direct inoculation of PBMC from infected patients, and in assays of antiviral drug effects. One of these cell lines, C8166-R5, is statistically not inferior to CD8-depleted PHA blasts for culturing HIV from the peripheral blood cells of patients. The effective concentrations of antiviral drugs of all classes were similar when assayed in C8166-R5 or PHA blasts. Known drug-resistant isolates grown in C8166-R5 demonstrated the predicted effects. We followed a patient longitudinally and demonstrated that resistance testing in C8166-R5 was predictive of clinical outcome. These experiments represent the first steps in developing a clinically useful phenotypic drug resistance assay based upon culturing the patient's own virus.

  4. Antiviral Defense Mechanisms in Honey Bees.

    Science.gov (United States)

    Brutscher, Laura M; Daughenbaugh, Katie F; Flenniken, Michelle L

    2015-08-01

    Honey bees are significant pollinators of agricultural crops and other important plant species. High annual losses of honey bee colonies in North America and in some parts of Europe have profound ecological and economic implications. Colony losses have been attributed to multiple factors including RNA viruses, thus understanding bee antiviral defense mechanisms may result in the development of strategies that mitigate colony losses. Honey bee antiviral defense mechanisms include RNA-interference, pathogen-associated molecular pattern (PAMP) triggered signal transduction cascades, and reactive oxygen species generation. However, the relative importance of these and other pathways is largely uncharacterized. Herein we review the current understanding of honey bee antiviral defense mechanisms and suggest important avenues for future investigation.

  5. E. fischeriana Root Compound Dpo Activates Antiviral Innate Immunity

    Directory of Open Access Journals (Sweden)

    Jingxuan Chen

    2017-10-01

    Full Text Available E. fischeriana has long been used as a traditional Chinese medicine. Recent studies reported that some compounds of E. fischeriana exhibited antimicrobial and immune enhance activity. Innate immune system is essential for the immune surveillance of inner and outer threats, initial host defense responses and immune modulation. The role of natural drug compounds, including E. fischeriana, in innate immune regulation is largely unknown. Here we demonstrated that E. fischeriana compound Dpo is involved in antiviral signaling. The genome wide RNA-seq analysis revealed that the induction of ISGs by viral infection could be synergized by Dpo. Consistently, Dpo enhanced the antiviral immune responses and protected the mice from death during viral infection. Dpo however was not able to rescue STING deficient mice lethality caused by HSV-1 infection. The enhancement of ISG15 by Dpo was also impaired in STING, IRF3, IRF7, or ELF4 deficient cells, demonstrating that Dpo activates innate immune responses in a STING/IRFs/ELF4 dependent way. The STING/IRFs/ELF4 axis is therefore important for Dpo induced ISGs expression, and can be used by host to counteract infection.

  6. The interferon response circuit in antiviral host defense.

    Science.gov (United States)

    Haller, O; Weber, F

    2009-01-01

    Viruses have learned to multiply in the face of a powerful innate and adaptive immune response of the host. They have evolved multiple strategies to evade the interferon (IFN) system which would otherwise limit virus growth at an early stage of infection. IFNs induce the synthesis of a range of antiviral proteins which serve as cell-autonomous intrinsic restriction factors. For example, the dynamin-like MxA GTPase inhibits the multiplication of influenza and bunyaviruses (such as La Crosse virus, Hantaan virus, Rift Valley Fever virus, and Crimean-Congo hemorrhagic fever virus) by binding and sequestering the nucleocapsid protein into large perinuclear complexes. To overcome such intracellular restrictions, virulent viruses either inhibit IFN synthesis, bind and inactivate secreted IFN molecules, block IFN-activated signaling, or disturb the action of IFN-induced antiviral proteins. Many viruses produce specialized proteins to disarm the danger signal or express virulence genes that target members of the IFN regulatory factor family (IRFs) or components of the JAK-STAT signaling pathway. An alternative evasion strategy is based on extreme viral replication speed which out-competes the IFN response. The identification of viral proteins with IFN antagonistic functions has great implications for disease prevention and therapy. Virus mutants lacking IFN antagonistic properties represent safe yet highly immunogenic candidate vaccines. Furthermore, novel drugs intercepting viral IFN-antagonists could be used to disarm the viral intruders.

  7. Japan-China Joint Medical Workshop on Drug Discoveries and Therapeutics 2008: The need of Asian pharmaceutical researchers' cooperation.

    Science.gov (United States)

    Nakata, M; Tang, W

    2008-10-01

    ) ● Spirohexalines A and B, novel undecaprenyl pyrophosphate inhibitors produced by Penicillium sp. FKI-3368 by Junji Inokoshi (Kitasato University, Japan) ● Nosokomycins, novel anti-MRSA antibiotics, produced by Streptomyces sp. K04-0144 by OR. Uchida (Kitasato University, Japan) ● In vivo screening for antimicrobial activity of Thai Herbal Medicines using silkworm model by Santad Chanprapaph (Chulalongkorn University, Thailand) ● Novel electrochemical sensor of nitric oxide for screening anti-aging Traditional Chinese Medicine by Zilin Chen (Wuhan University, China) ● Polysacchride from green tea purified by silkworm muscle contraction assay induces innate immunity by increasing the expression of various inflammatory cytokine mRNA in human leukocytes by Saphala Dhital (The University of Tokyo, Japan) Session IV. Anti-influenza Drugs ● Structure-activity relationship of flavonoids as influenza virus neuraminidase inhibitors and their in vitro anti-viral activities by Guanhua Du (Chinese Academy of Medical Sciences and Peking Union Medical College, China) ● Mechanisms and consequences of phagocytosis of influenza virus-infected cells by Yoshinobu Nakanishi (Kanazawa University, Japan) ● Nuclear export inhibitors; a possible target for novel anti-influenza viral drugs by Ken Watanabe (Nagasaki University, Japan) ● Catalytic asymmetric synthesis of oseltamivir phosphate directing toward its stable worldwide supply by Motomu Kanai (The University of Tokyo, Japan) ● Clinical effects of probiotic bifidobacterium in the prevention of influenza virus infections and allergic diseases by Jin-zhong Xiao (Morinaga Milk Industry Co., Ltd., Japan) ● Production of anti-influenza PR8-scFv using a phage display by Normaiza Zamri (Tokai University, Japan) Session V. Anti-infection/Antiviral Drugs ● Emerging infectious diseases and anti-viral drugs: Urgent need to develop effective drugs which cause less resistant virus by Nobuyuki Kobayashi (Nagasaki University

  8. Plants as sources of antiviral agents | Abonyi | African Journal of ...

    African Journals Online (AJOL)

    The use of plants or plant products, traditionally, as antiviral agents is relatively wider than their use in modern medicine. Some antiviral substances have so far been isolated from higher plants, algae and lichens. Suitable methods for evaluating antiviral properties of plants and their extracts include use of animal models, ...

  9. In vitro inhibition of canine distemper virus by flavonoids and phenolic acids: implications of structural differences for antiviral design.

    Science.gov (United States)

    Carvalho, O V; Botelho, C V; Ferreira, C G T; Ferreira, H C C; Santos, M R; Diaz, M A N; Oliveira, T T; Soares-Martins, J A P; Almeida, M R; Silva, A

    2013-10-01

    Infection caused by canine distemper virus (CDV) is a highly contagious disease with high incidence and lethality in the canine population. Antiviral activity of flavonoids quercetin, morin, rutin and hesperidin, and phenolic cinnamic, trans-cinnamic and ferulic acids were evaluated in vitro against the CDV using the time of addition assay to determine which step of the viral replicative cycle was affected. All flavonoids displayed great viral inhibition when they were added at the times 0 (adsorption) and 1h (penetration) of the viral replicative cycle. Both quercetin and hesperidin presented antiviral activity at the time 2h (intracellular). In the other hand, cinnamic acid showed antiviral activity at the times 0 and 2h while trans-cinnamic acid showed antiviral effect at the times -1h (pre-treatment) and 0 h. Ferulic acid inhibited CDV replicative cycle at the times 0 and 1h. Our study revealed promising candidates to be considered in the treatment of CDV. Structural differences among compounds and correlation to their antiviral activity were also explored. Our analysis suggest that these compounds could be useful in order to design new antiviral drugs against CDV as well as other viruses of great meaning in veterinary medicine. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. ANTIVIRAL EFFECT OF SELECTED MEDICINAL PLANTS 1 ...

    African Journals Online (AJOL)

    Methanolic extracts of the different morphological parts of three medicinal plants, Diospyros bateri, Diospyros monbutensis and Sphenocentrum jollyanum were evaluated for their antiviral activities on polio virus Types 1, 2, and 3. The leaf and root extracts of S. jollyanum, the seed extracts of D. monbutensis as well as the ...

  11. Curcumin Shows Antiviral Properties against Norovirus.

    Science.gov (United States)

    Yang, Minji; Lee, GilJae; Si, Jiyeon; Lee, Sung-Joon; You, Hyun Ju; Ko, GwangPyo

    2016-10-20

    Phytochemicals provide environmentally friendly and relatively inexpensive natural products, which could potentially benefit public health by controlling human norovirus (HuNoV) infection. In this study, 18 different phytochemicals were evaluated for antiviral effects against norovirus using murine norovirus (MNV) as a model for norovirus biology. Among these phytochemicals, curcumin (CCM) was the most potent anti-noroviral phytochemical, followed by resveratrol (RVT). In a cell culture infection model, exposure to CCM or RVT for 3 days reduced infectivity of norovirus by 91% and 80%, respectively. To confirm the antiviral capability of CCM, we further evaluated its antiviral efficacy at various doses (0.25, 0.5, 0.75, 1, and 2 mg/mL) and durations (short-term: 10, 30, 60, and 120 min; long-term: 1, 3, 7, and 14 days). The anti-noroviral effect of CCM was verified to occur in a dose-dependent manner. Additionally, we evaluated the inhibitory effect of each phytochemical on the replication of HuNoV using a HuNoV replicon-bearing cell line (HG23). Neither CCM nor RVT had a strong inhibitory effect on HuNoV replication, which suggests that their antiviral mechanism may involve viral entry or other life cycle stages rather than the replication of viral RNA. Our results demonstrated that CCM may be a promising candidate for development as an anti-noroviral agent to prevent outbreaks of foodborne illness.

  12. Antiviral effects of the milk protein lactoferrin

    NARCIS (Netherlands)

    Berkhout, B.; Floris, R.; Recio, I.; Visser, S.

    2003-01-01

    Milk forms a rich source of biologically interesting components and the protein fraction is known to facilitate many different biological functions. In this manuscript, we focus on the antiviral properties of the milk protein lactoferrin (LF), in particular against the human immunodeficiency virus

  13. Antiviral Prophylaxis and H1N1

    Centers for Disease Control (CDC) Podcasts

    2011-07-14

    Dr. Richard Pebody, a consultant epidemiologist at the Health Protection Agency in London, UK, discusses the use of antiviral post-exposure prophylaxis and pandemic H1N1.  Created: 7/14/2011 by National Center for Emerging Zoonotic and Infectious Diseases (NCEZID).   Date Released: 7/18/2011.

  14. Generation of antiviral transgenic chicken using spermatogonial ...

    African Journals Online (AJOL)

    This study was conducted in order to generate anti-viral transgenic chickens through transfected spermatogonial stem cell with fusion gene EGFP-MMx. After injecting fusion gene EGFP-MMx into testes, tissues frozen section, polymerase chain reaction (PCR) and dot blot of testes was performed at 30, 40, 50, 60, 70 and 80 ...

  15. Generation of antiviral transgenic chicken using spermatogonial ...

    African Journals Online (AJOL)

    DR TONUKARI NYEROVWO

    2011-11-09

    Nov 9, 2011 ... This study was conducted in order to generate anti-viral transgenic chickens through transfected spermatogonial stem cell with fusion gene EGFP-MMx. After injecting fusion gene EGFP-MMx into testes, tissues frozen section, polymerase chain reaction (PCR) and dot blot of testes was performed at. 30, 40 ...

  16. Mechanism of action of a pestivirus antiviral compound

    Science.gov (United States)

    Baginski, Scott G.; Pevear, Daniel C.; Seipel, Marty; Sun, Siu Chi Chang; Benetatos, Christopher A.; Chunduru, Srinivas K.; Rice, Charles M.; Collett, Marc S.

    2000-01-01

    We report here the discovery of a small molecule inhibitor of pestivirus replication. The compound, designated VP32947, inhibits the replication of bovine viral diarrhea virus (BVDV) in cell culture at a 50% inhibitory concentration of approximately 20 nM. VP32947 inhibits both cytopathic and noncytopathic pestiviruses, including isolates of BVDV-1, BVDV-2, border disease virus, and classical swine fever virus. However, the compound shows no activity against viruses from unrelated virus groups. Time of drug addition studies indicated that VP32947 acts after virus adsorption and penetration and before virus assembly and release. Analysis of viral macromolecular synthesis showed VP32947 had no effect on viral protein synthesis or polyprotein processing but did inhibit viral RNA synthesis. To identify the molecular target of VP32947, we isolated drug-resistant (DR) variants of BVDV-1 in cell culture. Sequence analysis of the complete genomic RNA of two DR variants revealed a single common amino acid change located within the coding region of the NS5B protein, the viral RNA-dependent RNA polymerase. When this single amino acid change was introduced into an infectious clone of drug-sensitive wild-type (WT) BVDV-1, replication of the resulting virus was resistant to VP32947. The RNA-dependent RNA polymerase activity of the NS5B proteins derived from WT and DR viruses expressed and purified from recombinant baculovirus-infected insect cells confirmed the drug sensitivity of the WT enzyme and the drug resistance of the DR enzyme. This work formally validates NS5B as a target for antiviral drug discovery and development. The utility of VP32947 and similar compounds for the control of pestivirus diseases, and for hepatitis C virus drug discovery efforts, is discussed. PMID:10869440

  17. Long time scale GPU dynamics reveal the mechanism of drug resistance of the dual mutant I223R/H275Y neuraminidase from H1N1-2009 influenza virus.

    Science.gov (United States)

    Woods, Christopher J; Malaisree, Maturos; Pattarapongdilok, Naruwan; Sompornpisut, Pornthep; Hannongbua, Supot; Mulholland, Adrian J

    2012-05-29

    Multidrug resistance of the pandemic H1N1-2009 strain of influenza has been reported due to widespread treatment using the neuraminidase (NA) inhibitors, oseltamivir (Tamiflu), and zanamivir (Relenza). From clinical data, the single I223R (IR(1)) mutant of H1N1-2009 NA reduced efficacy of oseltamivir and zanamivir by 45 and 10 times, (1) respectively. More seriously, the efficacy of these two inhibitors against the double mutant I223R/H275Y (IRHY(2)) was significantly reduced by a factor of 12 374 and 21 times, respectively, compared to the wild-type.(2) This has led to the question of why the efficacy of the NA inhibitors is reduced by the occurrence of these mutations and, specifically, why the efficacy of oseltamivir against the double mutant IRHY was significantly reduced, to the point where oseltamivir has become an ineffective treatment. In this study, 1 μs of molecular dynamics (MD) simulations was performed to answer these questions. The simulations, run using graphical processors (GPUs), were used to investigate the effect of conformational change upon binding of the NA inhibitors oseltamivir and zanamivir in the wild-type and the IR and IRHY mutant strains. These long time scale dynamics simulations demonstrated that the mechanism of resistance of IRHY to oseltamivir was due to the loss of key hydrogen bonds between the inhibitor and residues in the 150-loop. This allowed NA to transition from a closed to an open conformation. Oseltamivir binds weakly with the open conformation of NA due to poor electrostatic interactions between the inhibitor and the active site. The results suggest that the efficacy of oseltamivir is reduced significantly because of conformational changes that lead to the open form of the 150-loop. This suggests that drug resistance could be overcome by increasing hydrogen bond interactions between NA inhibitors and residues in the 150-loop, with the aim of maintaining the closed conformation, or by designing inhibitors that can form

  18. Mouse lung slices: An ex vivo model for the evaluation of antiviral and anti-inflammatory agents against influenza viruses.

    Science.gov (United States)

    Liu, Rui; An, Liwei; Liu, Ge; Li, Xiaoyu; Tang, Wei; Chen, Xulin

    2015-08-01

    The influenza A virus is notoriously known for its ability to cause recurrent epidemics and global pandemics. Antiviral therapy is effective when treatment is initiated within 48h of symptom onset, and delaying treatment beyond this time frame is associated with decreased efficacy. Research on anti-inflammatory therapy to ameliorate influenza-induced inflammation is currently underway and seems important to the impact on the clinical outcome. Both antiviral and anti-inflammatory drugs with novel mechanisms of action are urgently needed. Current methods for evaluating the efficacy of anti-influenza drugs rely mostly on transformed cells and animals. Transformed cell models are distantly related to physiological and pathological conditions. Although animals are the best choices for preclinical drug testing, they are not time- or cost-efficient. In this study, we established an ex vivo model using mouse lung slices to evaluate both antiviral and anti-inflammatory agents against influenza virus infection. Both influenza virus PR8 (H1N1) and A/Human/Hubei/3/2005 (H3N2) can replicate efficiently in mouse lung slices and trigger significant cytokine and chemokine responses. The induction of selected cytokines and chemokines were found to have a positive correlation between ex vivo and in vivo experiments, suggesting that the ex vivo cultured lung slices may closely resemble the lung functionally in an in vivo configuration when challenged by influenza virus. Furthermore, a set of agents with known antiviral and/or anti-inflammatory activities were tested to validate the ex vivo model. Our results suggested that mouse lung slices provide a robust, convenient and cost-efficient model for the assessment of both antiviral and anti-inflammatory agents against influenza virus infection in one assay. This ex vivo model may predict the efficacy of drug candidates' antiviral and anti-inflammatory activities in vivo. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. The antiviral effect of jiadifenoic acids C against coxsackievirus B3

    Directory of Open Access Journals (Sweden)

    Miao Ge

    2014-08-01

    Full Text Available Coxsackievirus B type 3 (CVB3 is one of the major causative pathogens associated with viral meningitis and myocarditis, which are widespread in the human population and especially prevalent in neonates and children. These infections can result in dilated cardiomyopathy (DCM and other severe clinical complications. There are no vaccines or drugs approved for the prevention or therapy of CVB3-induced diseases. During screening for anti-CVB3 candidates in our previous studies, we found that jiadifenoic acids C exhibited strong antiviral activities against CVB3 as well as other strains of Coxsackie B viruses (CVBs. The present studies were carried out to evaluate the antiviral activities of jiadifenoic acids C. Results showed that jiadifenoic acids C could reduce CVB3 RNA and proteins synthesis in a dose-dependent manner. Jiadifenoic acids C also had a similar antiviral effect on the pleconaril-resistant variant of CVB3. We further examined the impact of jiadifenoic acids C on the synthesis of viral structural and non-structural proteins, finding that jiadifenoic acids C could reduce VP1 and 3D protein production. A time-course study with Vero cells showed that jiadifenoic acids C displayed significant antiviral activities at 0–6 h after CVB3 inoculation, indicating that jiadifenoic acids C functioned at an early step of CVB3 replication. However, jiadifenoic acids C had no prophylactic effect against CVB3. Taken together, we show that jiadifenoic acids C exhibit strong antiviral activities against all strains of CVB, including the pleconaril-resistant variant. Our study could provide a significant lead for anti-CVB3 drug development.

  20. The Antiviral Mechanism of an Influenza A Virus Nucleoprotein-Specific Single-Domain Antibody Fragment

    Energy Technology Data Exchange (ETDEWEB)

    Hanke, Leo; Knockenhauer, Kevin E.; Brewer, R. Camille; van Diest, Eline; Schmidt, Florian I.; Schwartz, Thomas U.; Ploegh, Hidde L. (Whitehead); (MIT)

    2016-12-13

    Alpaca-derived single-domain antibody fragments (VHHs) that target the influenza A virus nucleoprotein (NP) can protect cells from infection when expressed in the cytosol. We found that one such VHH, αNP-VHH1, exhibits antiviral activity similar to that of Mx proteins by blocking nuclear import of incoming viral ribonucleoproteins (vRNPs) and viral transcription and replication in the nucleus. We determined a 3.2-Å crystal structure of αNP-VHH1 in complex with influenza A virus NP. The VHH binds to a nonconserved region on the body domain of NP, which has been associated with binding to host factors and serves as a determinant of host range. Several of the NP/VHH interface residues determine sensitivity of NP to antiviral Mx GTPases. The structure of the NP/αNP-VHH1 complex affords a plausible explanation for the inhibitory properties of the VHH and suggests a rationale for the antiviral properties of Mx proteins. Such knowledge can be leveraged for much-needed novel antiviral strategies.

    IMPORTANCEInfluenza virus strains can rapidly escape from protection afforded by seasonal vaccines or acquire resistance to available drugs. Additional ways to interfere with the virus life cycle are therefore urgently needed. The influenza virus nucleoprotein is one promising target for antiviral interventions. We have previously isolated alpaca-derived single-domain antibody fragments (VHHs) that protect cells from influenza virus infection if expressed intracellularly. We show here that one such VHH exhibits antiviral activities similar to those of proteins of the cellular antiviral defense (Mx proteins). We determined the three-dimensional structure of this VHH in complex with the influenza virus nucleoprotein and identified the interaction site, which overlaps regions that determine sensitivity of the virus to Mx proteins. Our data define a new vulnerability of influenza virus, help us to better understand the cellular antiviral mechanisms, and

  1. Targeting Innate Immunity for Antiviral Therapy through Small Molecule Agonists of the RLR Pathway

    Science.gov (United States)

    Pattabhi, Sowmya; Wilkins, Courtney R.; Dong, Ran; Knoll, Megan L.; Posakony, Jeffrey; Kaiser, Shari; Mire, Chad E.; Wang, Myra L.; Ireton, Renee C.; Geisbert, Thomas W.; Bedard, Kristin M.; Iadonato, Shawn P.

    2015-01-01

    selectively activate IRF3 for the purpose of identifying drug-like molecules that can be developed for the treatment of viral infections. Here, we report the discovery of a hydroxyquinoline family of small molecules that can activate IRF3 to promote cellular antiviral responses. These molecules can prophylactically or therapeutically control infection in cell culture by pathogenic RNA viruses, including West Nile virus, dengue virus, hepatitis C virus, influenza A virus, respiratory syncytial virus, Nipah virus, Lassa virus, and Ebola virus. Our study thus identifies a class of small molecules with a novel mechanism to enhance host immune responses for antiviral activity against a variety of RNA viruses that pose a significant health care burden and/or that are known to cause infections with high case fatality rates. PMID:26676770

  2. The Antiviral Mechanism of an Influenza A Virus Nucleoprotein-Specific Single-Domain Antibody Fragment.

    Science.gov (United States)

    Hanke, Leo; Knockenhauer, Kevin E; Brewer, R Camille; van Diest, Eline; Schmidt, Florian I; Schwartz, Thomas U; Ploegh, Hidde L

    2016-12-13

    Alpaca-derived single-domain antibody fragments (VHHs) that target the influenza A virus nucleoprotein (NP) can protect cells from infection when expressed in the cytosol. We found that one such VHH, αNP-VHH1, exhibits antiviral activity similar to that of Mx proteins by blocking nuclear import of incoming viral ribonucleoproteins (vRNPs) and viral transcription and replication in the nucleus. We determined a 3.2-Å crystal structure of αNP-VHH1 in complex with influenza A virus NP. The VHH binds to a nonconserved region on the body domain of NP, which has been associated with binding to host factors and serves as a determinant of host range. Several of the NP/VHH interface residues determine sensitivity of NP to antiviral Mx GTPases. The structure of the NP/αNP-VHH1 complex affords a plausible explanation for the inhibitory properties of the VHH and suggests a rationale for the antiviral properties of Mx proteins. Such knowledge can be leveraged for much-needed novel antiviral strategies. Influenza virus strains can rapidly escape from protection afforded by seasonal vaccines or acquire resistance to available drugs. Additional ways to interfere with the virus life cycle are therefore urgently needed. The influenza virus nucleoprotein is one promising target for antiviral interventions. We have previously isolated alpaca-derived single-domain antibody fragments (VHHs) that protect cells from influenza virus infection if expressed intracellularly. We show here that one such VHH exhibits antiviral activities similar to those of proteins of the cellular antiviral defense (Mx proteins). We determined the three-dimensional structure of this VHH in complex with the influenza virus nucleoprotein and identified the interaction site, which overlaps regions that determine sensitivity of the virus to Mx proteins. Our data define a new vulnerability of influenza virus, help us to better understand the cellular antiviral mechanisms, and provide a well-characterized tool to

  3. Clinical case of Successful Treatment by Antiviral Preparations of a Patient with Guillain — Barre Syndrome

    Directory of Open Access Journals (Sweden)

    E.Yu. Vinnyk

    2015-11-01

    Full Text Available There is described a clinical case of treatment of patients with acute Guillain — Barre syndrome of significant viral etiology. It was used the complex therapy with antiviral drugs according to the recommendations of the infectious disease specialist. In addition to basic therapy and plasma depletion, there were prescribed the preparation of acyclic nucleosides group, interferon and normal human immunoglobulin. The age of the latter significantly reduced the period of recovery of the patient and allow avoid complications.

  4. Sustained virological response to antiviral therapy reduces mortality in HCV reinfection after liver transplantation.

    Science.gov (United States)

    Picciotto, Francesco Paolo; Tritto, Giovanni; Lanza, Alfonso Galeota; Addario, Luigi; De Luca, Massimo; Di Costanzo, Giovan Giuseppe; Lampasi, Filippo; Tartaglione, Maria Teresa; Marsilia, Giuseppina Marino; Calise, Fulvio; Cuomo, Oreste; Ascione, Antonio

    2007-03-01

    HCV infection recurs almost in all HCV-positive patients receiving liver transplantation and carries a poor prognosis. Aim of this study was to analyze efficacy and effect on survival of antiviral therapy in this clinical setting. Pegylated-interferon alpha-2b and ribavirin were administered at a dose of 1 microg/kg of bwt weekly and 600-800 mg/day. Planned duration of treatment was 24 or 48 weeks according to HCV genotype. Patients who failed to respond at week 24 were considered as non-responders. 61 patients were enrolled. According to intention-to-treat analysis, 44 (72%) patients were considered as treatment failure (31 non-responders, 4 relapsers, 9 dropout). Sustained virological response was achieved in 17 cases (28%). Genotype 2, higher doses of antivirals and absence of histological cirrhosis were predictors of sustained virological response. In the follow up, patients with sustained virological response had a significantly lower mortality compared to patients with treatment failure (chi2=6.9; P<0.01). Response rate to antiviral therapy in HCV reinfection after liver transplantation is higher if a full dose of antiviral drugs is administered and if treatment starts before histological cirrhosis has developed. Sustained virological response improves patient survival.

  5. Antiviral activity of Petiveria alliacea against the bovine viral diarrhea virus.

    Science.gov (United States)

    Ruffa, M J; Perusina, M; Alfonso, V; Wagner, M L; Suriano, M; Vicente, C; Campos, R; Cavallaro, L

    2002-07-01

    Natural products are a relevant source of antiviral drugs. Five medicinal plants used in Argentina have been assayed to detect inhibition of viral growth. Antiviral activity of the infusions and methanolic extracts of Aristolochia macroura, Celtis spinosa, Plantago major, Schinus areira, Petiveria alliacea and four extracts obtained from the leaves and stems of the last plant were evaluated by the plaque assay. P. alliacea, unlike A. macroura, C. spinosa, P. major and S. areira, inhibited bovine viral diarrhea virus (BVDV) replication. Neither P. alliacea nor the assays of the other plants were active against herpes simplex virus type 1, poliovirus type 1, adenovirus serotype 7 and vesicular stomatitis virus type 1. Four extracts of P. alliacea were assayed to detect anti-BVDV activity. Ethyl acetate (EC(50) of 25 microg/ml) and dichloromethane (EC(50) of 43 microg/ml) extracts were active; moreover, promising SI (IC(50)/EC(50)) values were obtained. BVDV is highly prevalent in the cattle population, there are no antiviral compounds available; additionally, it is a viral model of the hepatitis C virus. For these reasons and in view of the results obtained, the isolation and characterization of the antiviral components present in the P. alliacea extracts is worth carrying out in the future. Copyright 2002 S. Karger AG, Basel

  6. Antiviral effect of cimicifugin from Cimicifuga foetida against human respiratory syncytial virus.

    Science.gov (United States)

    Wang, Kuo-Chih; Chang, Jung-San; Lin, Liang-Tzung; Chiang, Lien-Chai; Lin, Chun-Ching

    2012-01-01

    Human respiratory syncytial virus (RSV) causes serious infection of the lower respiratory tract in children and an effective antiviral therapy against the viral pathogen remains unavailable. We previously demonstrated that the oriental medicinal plant, Cimicifuga foetida L. (C. foetida), possessed inhibitory activity against RSV. Since cimicifugin is a major constituent of C. foetida, we sought to examine in this study its anti-RSV effect on both the human upper (HEp-2) and lower (A549) respiratory tract cell lines. Results revealed that cimicifugin dose-dependently inhibited RSV-induced plaque formation in both HEp-2 and A549 cells (p < 0.0001), with a superior effect in the latter cell type (p < 0.0001). The antiviral activity of cimicifugin was time-dependent (p < 0.0001) and was most effective when cells were treated with the compound before viral inoculation. Additional experiments demonstrated that cimicifugin could inhibit viral attachment (p < 0.0001) and viral internalization (p < 0.0001). Furthermore, the drug could potentiate heparin's effect against attachment of RSV, particularly in A549 cells. Enzyme-linked immunosorbent assay (ELISA) analysis of antiviral cytokines induction revealed that cimicifugin could also stimulate epithelial cells to secrete IFN-β to counteract viral infection. Taken together, these results indicate that cimicifugin is an efficient antiviral agent against RSV infection. We suggest that cimicifugin might be useful for the management of RSV pathogenesis.

  7. Antiviral Drug–Resistant Influenza B Viruses Carrying H134N Substitution in Neuraminidase, Laos, February 2016

    Science.gov (United States)

    Baranovich, Tatiana; Vongphrachanh, Phengta; Ketmayoon, Pakapak; Sisouk, Thongchanh; Chomlasack, Khampheng; Khanthamaly, Viengphone; Nguyen, Ha Thuy; Mishin, Vasiliy P.; Marjuki, Henju; Barnes, John R.; Garten, Rebecca J.; Stevens, James; Wentworth, David E.

    2017-01-01

    In February 2016, three influenza B/Victoria/2/87 lineage viruses exhibiting 4- to 158-fold reduced inhibition by neuraminidase inhibitors were detected in Laos. These viruses had an H134N substitution in the neuraminidase and replicated efficiently in vitro and in ferrets. Current antiviral drugs may be ineffective in controlling infections caused by viruses harboring this mutation. PMID:28322707

  8. Critical challenges and emerging opportunities in hepatitis C virus research in an era of potent antiviral therapy

    DEFF Research Database (Denmark)

    Bartenschlager, Ralf; Baumert, Thomas F.; Bukh, Jens

    2018-01-01

    The development and clinical implementation of direct-acting antivirals (DAAs) has revolutionized the treatment of chronic hepatitis C. Infection with any hepatitis C virus (HCV) genotype can now be eliminated in more than 95% of patients with short courses of all-oral, well-tolerated drugs, even...

  9. Oral antiviral drugs in experimental herpes simplex keratitis.

    OpenAIRE

    Kaufman, H E; Varnell, E D; Centifanto-Fitzgerald, Y M; De Clercq, E; Kissling, G E

    1983-01-01

    Chronic oral administration of acyclovir or bromovinyl deoxyuridine to rabbits did not prevent recurrence of virus shedding or clinical corneal disease, nor did it alter the clinical course of recurrences of ocular herpetic disease or result in the appearance of resistant virus in tears.

  10. Acyclic nucleoside phosphonates: A key class of antiviral drugs

    Czech Academy of Sciences Publication Activity Database

    De Clercq, E.; Holý, Antonín

    2005-01-01

    Roč. 4, č. 13 (2005), 928-940 ISSN 1474-1776 Institutional research plan: CEZ:AV0Z4055905 Keywords : tenofovir * adefovir * cidofovir Subject RIV: CC - Organic Chemistry Impact factor: 18.775, year: 2005

  11. What You Should Know about Flu Antiviral Drugs

    Science.gov (United States)

    ... congenital heart disease, congestive heart failure and coronary artery disease) Kidney disorders Liver disorders Metabolic disorders (such ... Privacy FOIA No Fear Act OIG 1600 Clifton Road Atlanta , GA 30329-4027 USA 800-CDC-INFO ( ...

  12. A community cluster of influenza A(H1N1)pdm09 virus exhibiting cross-resistance to oseltamivir and peramivir in Japan, November to December 2013.

    Science.gov (United States)

    Takashita, E; Ejima, M; Itoh, R; Miura, M; Ohnishi, A; Nishimura, H; Odagiri, T; Tashiro, M

    2014-01-09

    Six influenza A(H1N1)pdm09 viruses were detected in Sapporo, Japan, between November and December 2013. All six viruses possessed an H275Y substitution in the neuraminidase protein, which confers cross-resistance to oseltamivir and peramivir. No epidemiological link among the six cases could be identified; none of them had received neuraminidase inhibitors before specimen collection. The haemagglutinin and neuraminidase genes of the six viruses were closely related to one another, suggesting clonal spread of a single resistant virus.

  13. Separation methods for acyclovir and related antiviral compounds.

    Science.gov (United States)

    Loregian, A; Gatti, R; Palù, G; De Palo, E F

    2001-11-25

    Acyclovir (ACV) is an antiviral drug, which selectively inhibits replication of members of the herpes group of DNA viruses with low cell toxicity. Valaciclovir (VACV), a prodrug of ACV is usually preferred in the oral treatment of viral infections, mainly herpes simplex virus (HSV). Also other analogues such as ganciclovir and penciclovir are discussed here. The former acts against cytomegalovirus (CMV) in general and the latter against CMV retinitis. The action mechanism of these antiviral drugs is presented briefly here, mainly via phosphorylation and inhibition of the viral DNA polymerase. The therapeutic use and the pharmacokinetics are also outlined. The measurement of the concentration of acyclovir and related compounds in biological samples poses a particularly significant challenge because these drugs tend to be structurally similar to endogenous substances. The analysis requires the use of highly selective analytical techniques and chromatography methods are a first choice to determine drug content in pharmaceuticals and to measure them in body fluids. Chromatography can be considered the procedure of choice for the bio-analysis of this class of antiviral compounds, as this methodology is characterised by good specificity and accuracy and it is particularly useful when metabolites need to be monitored. Among chromatographic techniques, the reversed-phase (RP) HPLC is widely used for the analysis. C18 Silica columns from 7.5 to 30 cm in length are used, the separation is carried out mainly at room temperature and less than 10 min is sufficient for the analysis at 1.0-1.5 ml/min of flow-rate. The separation methods require an isocratic system, and various authors have proposed a variety of mobile phases. The detection requires absorbance or fluorescence measurements carried out at 250-254 nm and at lambdaex=260-285 nm, lambdaem=375-380 nm, respectively. The detection limit is about 0.3-10 ng/ml but the most important aspect is related to the sample treatment

  14. The effect of antiviral therapy on patients with hepatitis B virus-related hepatocellular carcinoma after curative resection: a systematic review and meta-analysis.

    Science.gov (United States)

    Chen, Xu-Xiao; Cheng, Jian-Wen; Huang, Ao; Zhang, Xin; Wang, Jian; Fan, Jia; Zhou, Jian; Yang, Xin-Rong

    2017-01-01

    Studies suggest that antiviral therapy performed after curative resection improves the postoperative prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), but the evidence has been contradictory. The aim of this meta-analysis was to assess the effect of antiviral therapy with nucleoside analogs (NAs) after curative resection on the long-term postoperative survival of patients with HBV-related HCC. MEDLINE, PubMed, Embase, and Cochrane Library were systematically searched up to August 2017 with no limits. Outcome measures were the primary parameter of overall survival (OS) after radical resection of HBV-related HCC and the secondary parameter of postoperative recurrence-free survival (RFS). A total of 9,009 patients (2,546 of whom received antiviral therapy and 6,463 received no treatment) were included. The pooled analysis revealed that antiviral therapy was associated with significantly improved OS (hazard ratio [HR]: 0.58; 95% confidence interval [CI]: 0.51-0.67; P antiviral drug. In the subgroup analysis, anti-viral therapy significantly prolonged both OS (HR: 0.69; 95% CI: 0.52-0.92; P =0.01) and RFS (HR: 0.58; 95% CI: 0.49-0.70; P Antiviral therapy with NAs confers significant survival benefits in patients with HBV-related HCC after curative resection, especially in patients with high baseline HBV DNA level (≥20,000 IU/mL).

  15. Steroid plus antiviral treatment for Bell's palsy.

    Science.gov (United States)

    Kang, H M; Jung, S Y; Byun, J Y; Park, M S; Yeo, S G

    2015-05-01

    The effectiveness of antiviral agents for the treatment of Bell's palsy is uncertain. We evaluated whether a steroid with an antiviral agent (S + A group) provided better recovery outcomes than a steroid alone (S group) in patients with Bell's palsy. A total of 1342 patients diagnosed with Bell's palsy who visited the Kyung Hee Medical Center in Seoul, Korea, from 2002 to 2012 were included in this study. Patients in the S + A group were treated with prednisolone and antiviral agents (n = 569) and those in the S group with prednisolone alone (n = 773). Outcomes were measured using the House-Brackmann (HB) scale according to age, initial disease severity, electroneurography (ENoG) findings and underlying comorbidities. The rate of recovery (HB grades I and II) with initially severe Bell's palsy (HB grades V and VI) was higher in the S + A than in the S group (P = 0.001). However, the rates of recovery were similar with initially moderate palsy (HB grades II-IV) (P = 0.502). In patients classified according to age and ENoG-determined severity of palsy, the overall recovery rate was higher in the S + A than in the S group, but the differences were not statistically significant (P > 0.05 for both). The recovery rate without diabetes mellitus (DM) and hypertension (HTN) was higher in the S + A group than in the S group (P = 0.031). But in the patients with HTN and DM, the difference in recovery rates between the S + A and S groups was not statistically significant (P = 0.805). Treatment with a steroid plus antiviral agent resulted in significantly higher recovery rates than steroid therapy alone in patients with initially severe Bell's palsy and without either HTN or DM, and a nonsignificant trend towards higher recovery rates in all patients with Bell's palsy in this study. Antiviral agents may therefore help in the treatment of Bell's palsy. © 2014 The Association for the Publication of the Journal of Internal Medicine.

  16. In Vitro Antiviral Effect of "Nanosilver" on Influenza Virus

    Directory of Open Access Journals (Sweden)

    P Mehrbod

    2009-08-01

    Full Text Available Introduction: Influenza is a viral infectious disease with frequent seasonal epidemics causing world-wide economical and social effects. Due to antigenic shifts and drifts of influenza virus, long-lasting vaccine has not been developed so far. The current annual vaccines and effective antiviral drugs are not available sufficiently. Therefore in order to prevent spread of infectious agents including viruses, antiseptics are considered by world health authorities. Small particles of silver have a long history as general antiseptic and disinfectant. Silver does not induce resistance in microorganisms and this ability in Nano-size is stronger. Materials and methods: The aim of this study was to determine antiviral effects of Nanosilver against influenza virus. TCID50 (50% Tissue Culture Infectious Dose of the virus as well as CC50 (50% Cytotoxic Concentration of Nanosilver was obtained by MTT (3- [4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide, Sigma method. This compound was non-toxic to MDCK (Madin-Darbey Canin Kidney cells at concentration up to 1 µg/ml.  Effective minimal cytotoxic concentration and 100 TCID50 of the virus were added to the confluent cells.  Inhibitory effects of Nanosilver on the virus and its cytotoxicity were assessed at different temperatures using Hemagglutination (HA assay, RT-PCR (Reverse Transcriptase-Polymerase Chain Reaction, and DIF (Direct Immunofluorescent. RT-PCR and free band densitometry software were used to compare the volume of the PCR product bands on the gel. Results and Discussion:  In this study it was found that Nanosilver has destructive effect on the virus membrane glycoprotein knobs as well as the cells.

  17. Arylazolyl(azinyl)thioacetanilide. Part 9: Synthesis and biological investigation of thiazolylthioacetamides derivatives as a novel class of potential antiviral agents.

    Science.gov (United States)

    Zhan, Peng; Wang, Liu; Liu, Hong; Chen, Xuwang; Li, Xiao; Jiang, Xin; Zhang, Qiangqiang; Liu, Xinyong; Pannecouque, Christophe; Naesens, Lieve; De Clercq, Erik; Liu, Ailin; Du, Guanhua

    2012-06-01

    In continuation of our endeavor to develop new, potent, selective and less toxic antiviral agents, a novel series of 2-(2-amino/chloro-4-(2,4-dibromophenyl) thiazol-5-ylthio)acetamide derivatives was synthesized via an expeditious route and evaluated for their anti-HIV activities against wild-type virus and clinically relevant mutant strains, and for their anti-influenza virus activities against influenza A (H1N1 and H3N2) and influenza B in cellular assays. The selected active compounds were also assayed for their enzymic inhibitory activities. The results showed that some 2-chloro substituted thiazolylthioacetamide derivatives possessed potent activity against wild type HIV-1 and several key mutant strains (E138K, K103N, L100I) of HIV-1 in MT-4 cells with EC(50) values in micromolar range. Two 2-amino substituted thiazole derivatives 8a7 and 8a8 displayed significant potency against influenza A/H1N1 in MDCK cells with EC(50) values much lower than that of oseltamivir carboxylate, ribavirin, amantadine and rimantadine. Though the mechanism of actions is still unclear, these novel thiazolylthioacetamides might serve as original leads for further pharmacological investigations as potential therapeutic agents against HIV-1 or influenza virus.

  18. Searching for synergy: Identifying optimal antiviral combination therapy using Hepatitis C virus (HCV) agents in a replicon system.

    Science.gov (United States)

    Pomeroy, Justin J; Drusano, George L; Rodriquez, Jaime L; Brown, Ashley N

    2017-10-01

    Direct acting antiviral agents (DAAs) are potent inhibitors of Hepatitis C virus (HCV) that have revolutionized the treatment landscape for this important viral disease. There are currently four classes of DAAs that inhibit HCV replication via distinct mechanisms of action: nonstructural protein (NS) 3/4a protease inhibitors, NS5A inhibitors, NS5B nucleoside polymerase inhibitors, and NS5B non-nucleoside polymerase inhibitors. Combination therapy with two or more DAAs has great potential to further enhance antiviral potency. The purpose of this study was to identify optimal combinations of DAAs against genotype 1 HCV replicons that maximized the inhibition of replicon replication. All possible two-drug combinations were evaluated against genotype 1a and 1b HCV replicons using a 96-well plate luciferase-based assay in triplicate. The Greco Universal Response Surface Area mathematical model was fit to the luciferase data to identify drug-drug interactions (i.e.: synergy, additivity, and antagonism) for antiviral effect against both genotypes. This information was used to rank-order combinations of DAAs based on their ability to inhibit replicon replication against genotype 1a and 1b HCV. These preclinical findings can provide information as to which antiviral regimens should move on in the development process. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Different Inhibitory Potencies of Oseltamivir Carboxylate, Zanamivir, and Several Tannins on Bacterial and Viral Neuraminidases as Assessed in a Cell-Free Fluorescence-Based Enzyme Inhibition Assay.

    Science.gov (United States)

    Quosdorf, Stefanie; Schuetz, Anja; Kolodziej, Herbert

    2017-11-17

    Neuraminidaseis a key enzyme in the life cycle of influenza viruses and is present in some bacterial pathogens. We here assess the inhibitory potency of plant tannins versus clinically used inhibitors on both a viral and a bacterial model neuraminidase by applying the 2'-(4-methylumbelliferyl)-α-d- N -acetylneuraminic acid (MUNANA)-based activity assay. A range of flavan-3-ols, ellagitannins and chemically defined proanthocyanidin fractions was evaluated in comparison to oseltamivir carboxylate and zanamivir for their inhibitory activities against viral influenza A (H1N1) and bacterial Vibrio cholerae neuraminidase (VCNA). Compared to the positive controls, all tested polyphenols displayed a weak inhibition of the viral enzyme but similar or even higher potency on the bacterial neuraminidase. Structure-activity relationship analyses revealed the presence of galloyl groups and the hydroxylation pattern of the flavan skeleton to be crucial for inhibitory activity. The combination of zanamivir and EPs ® 7630 (root extract of Pelargonium sidoides ) showed synergistic inhibitory effects on the bacterial neuraminidase. Co-crystal structures of VCNA with oseltamivir carboxylate and zanamivir provided insight into bacterial versus viral enzyme-inhibitor interactions. The current data clearly indicate that inhibitor potency strongly depends on the biological origin of the enzyme and that results are not readily transferable. The therapeutic relevance of our findings is briefly discussed.

  20. Different Inhibitory Potencies of Oseltamivir Carboxylate, Zanamivir, and Several Tannins on Bacterial and Viral Neuraminidases as Assessed in a Cell-Free Fluorescence-Based Enzyme Inhibition Assay

    Directory of Open Access Journals (Sweden)

    Stefanie Quosdorf

    2017-11-01

    Full Text Available Neuraminidase is a key enzyme in the life cycle of influenza viruses and is present in some bacterial pathogens. We here assess the inhibitory potency of plant tannins versus clinically used inhibitors on both a viral and a bacterial model neuraminidase by applying the 2′-(4-methylumbelliferyl-α-d-N-acetylneuraminic acid (MUNANA-based activity assay. A range of flavan-3-ols, ellagitannins and chemically defined proanthocyanidin fractions was evaluated in comparison to oseltamivir carboxylate and zanamivir for their inhibitory activities against viral influenza A (H1N1 and bacterial Vibrio cholerae neuraminidase (VCNA. Compared to the positive controls, all tested polyphenols displayed a weak inhibition of the viral enzyme but similar or even higher potency on the bacterial neuraminidase. Structure–activity relationship analyses revealed the presence of galloyl groups and the hydroxylation pattern of the flavan skeleton to be crucial for inhibitory activity. The combination of zanamivir and EPs® 7630 (root extract of Pelargonium sidoides showed synergistic inhibitory effects on the bacterial neuraminidase. Co-crystal structures of VCNA with oseltamivir carboxylate and zanamivir provided insight into bacterial versus viral enzyme-inhibitor interactions. The current data clearly indicate that inhibitor potency strongly depends on the biological origin of the enzyme and that results are not readily transferable. The therapeutic relevance of our findings is briefly discussed.

  1. Inkjet printing of antiviral PCL nanoparticles and anticancer cyclodextrin inclusion complexes on bioadhesive film for cervical administration.

    Science.gov (United States)

    Varan, Cem; Wickström, Henrika; Sandler, Niklas; Aktaş, Yeşim; Bilensoy, Erem

    2017-10-15

    Personalized medicine is an important treatment approach for diseases like cancer with high intrasubject variability. In this framework, printing is one of the most promising methods since it permits dose and geometry adjustment of the final product. With this study, a combination product consisting of anticancer (paclitaxel) and antiviral (cidofovir) drugs was manufactured by inkjet printing onto adhesive film for local treatment of cervical cancers as a result of HPV infection. Furthermore, solubility problem of paclitaxel was overcome by maintaining this poorly soluble drug in a cyclodextrin inclusion complex and release of cidofovir was controlled by encapsulation in polycaprolactone nanoparticles. In vitro characterization studies of printed film formulations were performed and cell culture studies showed that drug loaded film formulation was effective on human cervical adenocarcinoma cells. Our study suggests that inkjet printing technology can be utilized in the development of antiviral/anticancer combination dosage forms for mucosal application. The drug amount in the delivery system can be accurately controlled and modified. Moreover, prolonged drug release time can be obtained. Printing of anticancer and antiviral drugs on film seem to be a potential approach for HPV-related cervical cancer treatment and a good candidate for further studies. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. An innate antiviral pathway acting before interferons at epithelial surfaces

    DEFF Research Database (Denmark)

    Iversen, Marie B; Reinert, Line S; Thomsen, Martin K

    2016-01-01

    we identify an innate antiviral pathway that works at epithelial surfaces before the IFNs. The pathway is activated independently of known innate sensors of viral infections through a mechanism dependent on viral O-linked glycans, which induce CXCR3 chemokines and stimulate antiviral activity...... in a manner dependent on neutrophils. This study therefore identifies a previously unknown layer of antiviral defense that exerts its action on epithelial surfaces before the classical IFN response is operative....

  3. Antiviral Effect of Sub Fraction Cassia alata Leaves Extract to Dengue Virus Serotype-2 strain New Guinea C in Human Cell Line Huh-7 it-1

    Science.gov (United States)

    Angelina, Marissa; Hanafi, Muhammad; Suyatna, Franciscus D.; Mirawati S., T.; Ratnasari, Shirley; Ernawati Dewi, Beti

    2017-12-01

    Dengue virus (DENV) is one of the most common viral infections found Indonesia and tropical regions, and no specific antiviral for DENV. Indonesia has several of herbal medicine that were not explored of their potency as antiviral DENV. This study was done to evaluate the activity and toxicity of 4 derived fractions: Hexane (CA1), ethyl acetate (CA2), buthanol (CA3 ) and water (CA4) of Cassia alata leaf extract (CA) as an antiviral drug to DENV. The DENV was treated with various concentration of extract and added to Huh-7 it-1. The decrease of virus titer was determined by Focus assay. The toxicity of extract was measured by MTT assay. In our previous study, we found that CA on Huh-7 cells showed IC50, CC50 and SI values of <10 μg/mL, 323.45 μg/mL, and more than 32.3, respectively. For the fractions, CA3 showed best antiviral activity among other, with IC50, CC50 and SI of <10 μg/mL, 645.8 μg/mL, and more than 64.5, respectively. CA and CA3 were proven to possess antiviral activity that is potent when tested against DENV-2. Future study was needed to explore the inhibition mechanism and compound of CA that have potency as antiviral drug to DENV.

  4. Hydrogen bonds and antiviral activity of benzaldehyde derivatives

    Science.gov (United States)

    Tolstorozhev, G. B.; Skornyakov, I. V.; Belkov, M. V.; Shadyro, O. I.; Brinkevich, S. D.; Samovich, S. N.

    2012-09-01

    We have obtained the Fourier transform IR spectra of solutions of benzaldehyde derivatives having different antiviral activities against a herpes virus. We observe a correlation between the presence of hydrogen bonds in the benzaldehyde molecules and the appearance of antiviral properties in the compounds. For compounds having antiviral activity, we have obtained spectral data suggesting the existence of hydrogen bonds of the type C=OṡṡṡH-O and O-HṡṡṡO in the molecules. When the hydrogen atom in the hydroxyl groups are replaced by a methyl group, no intramolecular hydrogen bonds are formed and the compounds lose their antiviral activity.

  5. Systems biology: A tool for charting the antiviral landscape.

    Science.gov (United States)

    Bowen, James R; Ferris, Martin T; Suthar, Mehul S

    2016-06-15

    The host antiviral programs that are initiated following viral infection form a dynamic and complex web of responses that we have collectively termed as "the antiviral landscape". Conventional approaches to studying antiviral responses have primarily used reductionist systems to assess the function of a single or a limited subset of molecules. Systems biology is a holistic approach that considers the entire system as a whole, rather than individual components or molecules. Systems biology based approaches facilitate an unbiased and comprehensive analysis of the antiviral landscape, while allowing for the discovery of emergent properties that are missed by conventional approaches. The antiviral landscape can be viewed as a hierarchy of complexity, beginning at the whole organism level and progressing downward to isolated tissues, populations of cells, and single cells. In this review, we will discuss how systems biology has been applied to better understand the antiviral landscape at each of these layers. At the organismal level, the Collaborative Cross is an invaluable genetic resource for assessing how genetic diversity influences the antiviral response. Whole tissue and isolated bulk cell transcriptomics serves as a critical tool for the comprehensive analysis of antiviral responses at both the tissue and cellular levels of complexity. Finally, new techniques in single cell analysis are emerging tools that will revolutionize our understanding of how individual cells within a bulk infected cell population contribute to the overall antiviral landscape. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Understanding and addressing hepatitis C reinfection in the oral direct-acting antiviral era.

    Science.gov (United States)

    Falade-Nwulia, O; Sulkowski, M S; Merkow, A; Latkin, C; Mehta, S H

    2018-03-01

    The availability of effective, simple, well-tolerated oral direct-acting antiviral (DAA) hepatitis C regimens has raised optimism for hepatitis C virus (HCV) elimination at the population level. HCV reinfection in key populations such as people who inject drugs (PWID) and HIV-infected men who have sex with men (MSM) however threatens the achievement of this goal from a patient, provider and population perspective. The goal of this review was to synthesize our current understanding of estimated rates and factors associated with HCV reinfection. This review also proposes interventions to aid understanding of and reduce hepatitis C reinfection among PWID and HIV-infected MSM in the oral direct-acting antiviral era. © 2018 John Wiley & Sons Ltd.

  7. Antiviral potential of medicinal plants against HIV, HSV, influenza, hepatitis, and coxsackievirus: A systematic review.

    Science.gov (United States)

    Akram, Muhammad; Tahir, Imtiaz Mahmood; Shah, Syed Muhammad Ali; Mahmood, Zahed; Altaf, Awais; Ahmad, Khalil; Munir, Naveed; Daniyal, Muhammad; Nasir, Suhaila; Mehboob, Huma

    2018-01-22

    Viral infections are being managed therapeutically through available antiviral regimens with unsatisfactory clinical outcomes. The refractory viral infections resistant to available antiviral drugs are alarming threats and a serious health concern. For viral hepatitis, the interferon and vaccine therapies solely are not ultimate solutions due to recurrence of hepatitis C virus. Owing to the growing incidences of viral infections and especially of resistant viral strains, the available therapeutic modalities need to be improved, complemented with the discovery of novel antiviral agents to combat refractory viral infections. It is widely accepted that medicinal plant heritage is nature gifted, precious, and fueled with the valuable resources for treatment of metabolic and infectious disorders. The aims of this review are to assemble the facts and to conclude the therapeutic potential of medicinal plants in the eradication and management of various viral diseases such as influenza, human immunodeficiency virus (HIV), herpes simplex virus (HSV), hepatitis, and coxsackievirus infections, which have been proven in diverse clinical studies. The articles, published in the English language since 1982 to 2017, were included from Web of Science, Cochrane Library, AMED, CISCOM, EMBASE, MEDLINE, Scopus, and PubMed by using relevant keywords including plants possessing antiviral activity, the antiviral effects of plants, and plants used in viral disorders. The scientific literature mainly focusing on plant extracts and herbal products with therapeutic efficacies against experimental models of influenza, HIV, HSV, hepatitis, and coxsackievirus were included in the study. Pure compounds possessing antiviral activity were excluded, and plants possessing activity against viruses other than viruses in inclusion criteria were excluded. Hundreds of plant extracts with antiviral effect were recognized. However, the data from only 36 families investigated through in vitro and in vivo

  8. Atividade antiviral de Musa acuminata Colla, Musaceae

    Directory of Open Access Journals (Sweden)

    Fernanda Otaviano Martins

    Full Text Available O presente trabalho avalia a atividade antiviral de extratos e frações de Musa acuminata Colla, Musaceae, coletada em duas regiões do Estado do Rio de Janeiro (Petrópolis e Santo Antônio de Pádua. As inflorescências de M. acuminata apresentaram excelente atividade para os dois vírus avaliados: herpesvírus simples humano tipo 1 e herpesvírus simples humano tipo 2, ambos resistentes ao Aciclovir. Os resultados indicam que os extratos de M. acuminata testados podem constituir alvo potencial para uso em terapias antivirais.

  9. Electronic absorption spectra of antiviral aminophenol derivatives

    Science.gov (United States)

    Belkov, M. V.; Ksendzova, G. A.; Raichyonok, T. F.; Skornyakov, I. V.; Sorokin, V. L.; Tolstorozhev, G. B.; Shadyro, O. I.

    2011-03-01

    Electronic absorption spectra of aminophenol derivatives in solutions have been studied. A general property of the absorption spectra of these compounds, the dependence of the maximum of a long-wavelength absorption band on the solvent polarity, is revealed. As a rule, the absorption band maximum of compounds possessing pharmacological properties shows a greater shift to short wavelength with an increase in the medium polarity than that of inactive compounds. Absorption measurements of solutions of aminophenol derivatives can be used for a tentative estimation of their antiviral activity.

  10. Antitheilerial Chemical Drugs: A Review | Hayat | Bulletin of Animal ...

    African Journals Online (AJOL)

    Synthetic or semi synthetic chemical drugs were used for treatment of Theileria species. These drugs include antimalarial, trypanocides and antibiotics, antiviral, etc. The aim of this study was to over-view chemical drugs tested for treatment of theileriosis. Keywords: Theileria, treatment, chemical drug ...

  11. Ensuring safe drug administration to pediatric patients with renal dysfunction: a multicenter study.

    Science.gov (United States)

    Harada, Ryoko; Ishikura, Kenji; Shinozuka, Shunsuke; Mikami, Naoaki; Hamada, Riku; Hataya, Hiroshi; Morikawa, Yoshihiko; Omori, Tae; Takahashi, Hirotaka; Hamasaki, Yuko; Kaneko, Tetsuji; Iijima, Kazumoto; Honda, Masataka

    2018-02-06

    In pediatric patients, due to variations in baseline serum creatinine (Cr) reference values, renal dysfunctions sometimes go unnoticed. In addition, renally excreted drugs need dose adjustment while nephrotoxic drugs should be avoided altogether in patients with impaired renal function. However, most physicians are apparently unaware of these facts and may administer these drugs to vulnerable patients. We administered a questionnaire to all physicians and pharmacists specializing in pediatric medical care at six Tokyo metropolitan government-run hospitals in Japan. 276 (59%) of 470 physicians and pharmacists participated. The rate of correct answers given by physicians who were asked to state the serum Cr reference range for 4-year-olds and 8-year-olds was 83 and 74%, respectively. On the other hand, the rate of correct answers given by pharmacists to the same question was only 27 and 24%, respectively. Only about 50% of physicians were aware that histamine H 2 -receptor antagonists and oseltamivir are renally excreted or that acyclovir and angiotensin II receptor blocker are nephrotoxic. However, most of the pharmacists recognized that histamine H 2 -receptor antagonists and oseltamivir are renally excreted drugs. For the majority of the investigated drugs, the awareness that we need to reduce dosages for patients with renal dysfunction was insufficient. To ensure safe drug administration, communication between physicians and pharmacists is paramount. There is an urgent need for the creation of a safe drug administration protocol for pediatric patients with renal dysfunction.

  12. New alloferon analogues: synthesis and antiviral properties.

    Science.gov (United States)

    Kuczer, Mariola; Majewska, Anna; Zahorska, Renata

    2013-02-01

    We have extended our study on structure/activity relationship studies of insect peptide alloferon (H-His-Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-His-Gly-OH) by evaluating the antiviral effects of new alloferon analogues. We synthesized 18 alloferon analogues: 12 peptides with sequences shortened from N- or C-terminus and 6 N-terminally modified analogues H-X(1)-Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-His-Gly-OH, where X(1) = Phe (13), Tyr (14), Trp (15), Phg (16), Phe(p-Cl) (17), and Phe(p-OMe) (18). We found that most of the evaluated peptides inhibit the replication of Human Herpesviruses or Coxsackievirus B2 in Vero, HEp-2 and LLC-MK(2) cells. Our results indicate that the compound [3-13]-alloferon (1) exhibits the strongest antiviral activity (IC(50) = 38 μM) among the analyzed compound. Moreover, no cytotoxic activity against the investigated cell lines was observed for all studied peptides at concentration 165 μM or higher. © 2012 John Wiley & Sons A/S.

  13. Molecular strategies to design an escape-proof antiviral therapy

    NARCIS (Netherlands)

    Berkhout, Ben; Sanders, Rogier W.

    2011-01-01

    Two antiviral approaches against the human immunodeficiency virus type 1 (HIV-1) were presented at the Antivirals Congress in Amsterdam. The common theme among these two separate therapeutic research lines is the wish to develop a durable therapy that prevents viral escape. We will present a brief

  14. In vitro antiviral activity of Orthosiphon stamineus extract against ...

    African Journals Online (AJOL)

    In vitro antiviral activity of Orthosiphon stamineus extract against dengue virus type 2. ... Journal of Fundamental and Applied Sciences ... The antiviral activity towards Dengue virus type 2 (DENV-2) was investigated by observing the morphological changes, which were further confirmed the cellular viability evaluated by ...

  15. Antiviral activities of streptomycetes against tobacco mosaic virus ...

    African Journals Online (AJOL)

    Antiviral activities of streptomycetes against tobacco mosaic virus (TMV) in Datura plant: Evaluation of different organic compounds in their metabolites. ... of different compounds. Key words: Antiviral activity, tobacco mosaic virus, actinomycetes, Streptomyces, Datura metel, GC-MS analysis, human pathogenic bacteria.

  16. Antiviral activity and mechanism of action of arbidol against Hantaan ...

    African Journals Online (AJOL)

    Keywords: Hantavirus, Arbidol, Toll-like receptors, inducible nitric oxide synthase, Antiviral activity, ... hantavirus infection. Arbidol is a broad-spectrum antiviral compound that has been shown to have inhibitory effect on influenza virus [4,5], respiratory syncytial virus [6], ..... species in hantavirus cardiopulmonary syndrome.

  17. Anti-viral effect of herbal medicine Korean traditional Cynanchum ...

    African Journals Online (AJOL)

    Background: Pestiviruses in general, and Bovine Viral Diarrhea (BVD) in particular, present several potential targets for directed antiviral therapy. Material and Methods: The antiviral effect of Cynanchum paniculatum (Bge.) Kitag (Dog strangling vine: DS) extract on the bovine viral diarrhea (BVD) virus was tested. First ...

  18. Antivirals Market Offering High-growth Opportunities for Market Players

    OpenAIRE

    Smita Deshmukh

    2016-01-01

    Transparency Market Research Reports incorporated a definite business overview and investigation inclines on "Antivirals Market". This report likewise incorporates more illumination about fundamental review of the business including definitions, requisitions and worldwide business sector industry structure. Read Full Report: http://www.transparencymarketresearch.com/antivirals-market.html

  19. Plants as sources of antiviral agents | Abonyi | African Journal of ...

    African Journals Online (AJOL)

    Antivirals are substances other than a virus or virus containing vaccine or specific antibody which can produce either a protective or therapeutic effect to the clear detectable advantage of the virus infected host. The search for antiviral agents began in earnest in the 1950s but this was directed mainly by chance, with little or ...

  20. Development of a Broad-Spectrum Antiviral Agent with Activity ...

    African Journals Online (AJOL)

    Development of a Broad-Spectrum Antiviral Agent with Activity Against Herpesvirus Replication and Gene Expression. ... Tropical Journal of Pharmaceutical Research ... Purpose: To evaluate the broad-spectrum antiviral activity of peptide H9 (H9) in vitro in order to gain insight into its underlying molecular mechanisms.

  1. Continuous Morbidity Registration at Dutch Sentinel Stations 2007.

    NARCIS (Netherlands)

    Donker, G.A.

    2007-01-01

    The flu epidemic in the winter of 2007/2008 was less severe but lasted longer than the epidemic of the previous year. Unexpectedly, 27% of the AH1N1 influenza viruses found last year proved to be resistant to the antiviral drug oseltamivir (Tamiflu). AH1N1 was the most common strain found during the

  2. New Class of Monoclonal Antibodies against Severe Influenza: Prophylactic and Therapeutic Efficacy in Ferrets

    NARCIS (Netherlands)

    Friesen, Robert H. E.; Koudstaal, Wouter; Koldijk, Martin H.; Weverling, Gerrit Jan; Brakenhoff, Just P. J.; Lenting, Peter J.; Stittelaar, Koert J.; Osterhaus, Albert D. M. E.; Kompier, Ronald; Goudsmit, Jaap

    2010-01-01

    BACKGROUND: The urgent medical need for innovative approaches to control influenza is emphasized by the widespread resistance of circulating subtype H1N1 viruses to the leading antiviral drug oseltamivir, the pandemic threat posed by the occurrences of human infections with highly pathogenic avian

  3. New class of monoclonal antibodies against severe influenza: Prophylactic and therapeutic efficacy in ferrets

    NARCIS (Netherlands)

    R.H.E. Friesen (Robert); W. Koudstaal (Wouter); M.H. Koldijk (Martin); G.J. Weverling (Gerrit); J.P. Brakenhoff (Just); P.J. Lenting (Peter); K.J. Stittelaar (Koert); A.D.M.E. Osterhaus (Albert); R. Kompier (Ronald); J. Goudsmit (Jaap)

    2010-01-01

    textabstractBackground: The urgent medical need for innovative approaches to control influenza is emphasized by the widespread resistance of circulating subtype H1N1 viruses to the leading antiviral drug oseltamivir, the pandemic threat posed by the occurrences of human infections with highly

  4. Drug susceptibility of influenza A/H3N2 strains co-circulating during 2009 influenza pandemic: first report from Mumbai.

    Science.gov (United States)

    Gohil, Devanshi J; Kothari, Sweta T; Shinde, Pramod S; Chintakrindi, Anand S; Meharunkar, Rhuta; Warke, Rajas V; Kanyalkar, Meena A; Chowdhary, Abhay S; Deshmukh, Ranjana A

    2015-01-01

    From its first instance in 1977, resistance to amantadine, a matrix (M2) inhibitor has been increasing among influenza A/H3N2, thus propelling the use of oseltamivir, a neuraminidase (NA) inhibitor as a next line drug. Information on drug susceptibility to amantadine and neuraminidase inhibitors for influenza A/H3N2 viruses in India is limited with no published data from Mumbai. This study aimed at examining the sensitivity to M2 and NA inhibitors of influenza A/H3N2 strains isolated from 2009 to 2011 in Mumbai. Nasopharyngeal swabs positive for influenza A/H3N2 virus were inoculated on Madin-Darby canine kidney (MDCK) cell line for virus isolation. Molecular analysis of NA and M2 genes was used to detect known mutations contributing to resistance. Resistance to neuraminidase was assayed using a commercially available chemiluminescence based NA-Star assay kit. Genotypically, all isolates were observed to harbor mutations known to confer resistance to amantadine. However, no know mutations conferring resistance to NA inhibitors were detected. The mean IC50 value for oseltamivir was 0.25 nM. One strain with reduced susceptibility to the neuraminidase inhibitor (IC₅₀=4.08 nM) was isolated from a patient who had received oseltamivir treatment. Phylogenetic analysis postulate the emergence of amantadine resistance in Mumbai may be due to genetic reassortment with the strains circulating in Asia and North America. Surveillance of drug susceptibility helped us to identify an isolate with reduced sensitivity to oseltamivir. Therefore, we infer that such surveillance would help in understanding possible trends underlying the emergence of resistant variants in humans. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Drug: D08778 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08778 Drug Freeze-dried, inactivated hepatitis A vaccine (JAN); Freeze-dried inac...tivated tissue cluture hepatitis A vaccine; Aimmugen (TN) ... Antiviral ... DG01686 ... Inactivated vaccine Therapeutic category: 6313 ATC code: J07BC02 ... PubChem: 96025461 ...

  6. Drug: D10193 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10193 Drug Live attenuated human rota virus vaccine, oral; Rotarix (TN) ... Antiviral ... DG01689 ... Live vac...cine ... DG01688 ... Oral live vaccine Therapeutic category: 6313 ATC code: J07BH01 ... G1 and non-G1 (G3, G4, and G9) types ... PubChem: 135626911 ...

  7. Drug: D09725 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D09725 Drug Emulsified influenza HA vaccine (A/H1N1); Arepanrix (H1N1) (TN) ... ...Antiviral ... DG01686 ... Inactivated vaccine ATC code: J07BB02 ... H1N1 influenza ... PubChem: 124490465 ...

  8. Drug: D10211 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10211 Drug Rotavirus vaccine, live, oral, pentavalent; Rotateq (TN) ... Antiviral ... DG01689 ... Live vaccine... ... DG01688 ... Oral live vaccine Therapeutic category: 6313 ATC code: J07BH02 ... Serotypes G1, G2, G3, and G4 ... PubChem: 163312242 ...

  9. Drug: D05089 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D05089 Drug Freeze-dried live attenuated mumps vaccine (JP17); Freeze-dried live attenuated mumps vaccine... (TN) ... Antiviral ... DG01689 ... Live vaccine ... DG01687 ... Parenteral live vaccine Therapeutic category: 6313 ATC code: J07BE01 ... PubChem: 17398246 ...

  10. Drug: D06466 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D06466 Drug Freeze-dried BCG vaccine (for percutaneous use) (JP17); Immunobladder ...(TN) ... Antiviral ... DG01689 ... Live vaccine ... DG01687 ... Parenteral live vaccine Therapeutic category: 6311 6391 ATC code: L03AX03 Chemical group: DG00738 ... PubChem: 47208122 ...

  11. Assessment of the antiviral properties of recombinant porcine SP-D against various influenza A viruses in vitro.

    Science.gov (United States)

    Hillaire, Marine L B; van Eijk, Martin; van Trierum, Stella E; van Riel, Debby; Saelens, Xavier; Romijn, Roland A; Hemrika, Wieger; Fouchier, Ron A M; Kuiken, Thijs; Osterhaus, Albert D M E; Haagsman, Henk P; Rimmelzwaan, Guus F

    2011-01-01

    The emergence of influenza viruses resistant to existing classes of antiviral drugs raises concern and there is a need for novel antiviral agents that could be used therapeutically or prophylacticaly. Surfactant protein D (SP-D) belongs to the family of C-type lectins which are important effector molecules of the innate immune system with activity against bacteria and viruses, including influenza viruses. In the present study we evaluated the potential of recombinant porcine SP-D as an antiviral agent against influenza A viruses (IAVs) in vitro. To determine the range of antiviral activity, thirty IAVs of the subtypes H1N1, H3N2 and H5N1 that originated from birds, pigs and humans were selected and tested for their sensitivity to recombinant SP-D. Using these viruses it was shown by hemagglutination inhibition assay, that recombinant porcine SP-D was more potent than recombinant human SP-D and that especially higher order oligomeric forms of SP-D had the strongest antiviral activity. Porcine SP-D was active against a broad range of IAV strains and neutralized a variety of H1N1 and H3N2 IAVs, including 2009 pandemic H1N1 viruses. Using tissue sections of ferret and human trachea, we demonstrated that recombinant porcine SP-D prevented attachment of human seasonal H1N1 and H3N2 virus to receptors on epithelial cells of the upper respiratory tract. It was concluded that recombinant porcine SP-D holds promise as a novel antiviral agent against influenza and further development and evaluation in vivo seems warranted.

  12. Assessment of the antiviral properties of recombinant porcine SP-D against various influenza A viruses in vitro.

    Directory of Open Access Journals (Sweden)

    Marine L B Hillaire

    Full Text Available The emergence of influenza viruses resistant to existing classes of antiviral drugs raises concern and there is a need for novel antiviral agents that could be used therapeutically or prophylacticaly. Surfactant protein D (SP-D belongs to the family of C-type lectins which are important effector molecules of the innate immune system with activity against bacteria and viruses, including influenza viruses. In the present study we evaluated the potential of recombinant porcine SP-D as an antiviral agent against influenza A viruses (IAVs in vitro. To determine the range of antiviral activity, thirty IAVs of the subtypes H1N1, H3N2 and H5N1 that originated from birds, pigs and humans were selected and tested for their sensitivity to recombinant SP-D. Using these viruses it was shown by hemagglutination inhibition assay, that recombinant porcine SP-D was more potent than recombinant human SP-D and that especially higher order oligomeric forms of SP-D had the strongest antiviral activity. Porcine SP-D was active against a broad range of IAV strains and neutralized a variety of H1N1 and H3N2 IAVs, including 2009 pandemic H1N1 viruses. Using tissue sections of ferret and human trachea, we demonstrated that recombinant porcine SP-D prevented attachment of human seasonal H1N1 and H3N2 virus to receptors on epithelial cells of the upper respiratory tract. It was concluded that recombinant porcine SP-D holds promise as a novel antiviral agent against influenza and further development and evaluation in vivo seems warranted.

  13. Hepatitis C virus cell-cell transmission and resistance to direct-acting antiviral agents.

    Directory of Open Access Journals (Sweden)

    Fei Xiao

    2014-05-01

    Full Text Available Hepatitis C virus (HCV is transmitted between hepatocytes via classical cell entry but also uses direct cell-cell transfer to infect neighboring hepatocytes. Viral cell-cell transmission has been shown to play an important role in viral persistence allowing evasion from neutralizing antibodies. In contrast, the role of HCV cell-cell transmission for antiviral resistance is unknown. Aiming to address this question we investigated the phenotype of HCV strains exhibiting resistance to direct-acting antivirals (DAAs in state-of-the-art model systems for cell-cell transmission and spread. Using HCV genotype 2 as a model virus, we show that cell-cell transmission is the main route of viral spread of DAA-resistant HCV. Cell-cell transmission of DAA-resistant viruses results in viral persistence and thus hampers viral eradication. We also show that blocking cell-cell transmission using host-targeting entry inhibitors (HTEIs was highly effective in inhibiting viral dissemination of resistant genotype 2 viruses. Combining HTEIs with DAAs prevented antiviral resistance and led to rapid elimination of the virus in cell culture model. In conclusion, our work provides evidence that cell-cell transmission plays an important role in dissemination and maintenance of resistant variants in cell culture models. Blocking virus cell-cell transmission prevents emergence of drug resistance in persistent viral infection including resistance to HCV DAAs.

  14. Antiviral activity of a Bacillus sp: P34 peptide against pathogenic viruses of domestic animals

    Directory of Open Access Journals (Sweden)

    Débora Scopel e Silva

    2014-09-01

    Full Text Available P34 is an antimicrobial peptide produced by a Bacillus sp. strain isolated from the intestinal contents of a fish in the Brazilian Amazon basin with reported antibacterial activity. The aim of this work was to evaluate the peptide P34 for its in vitro antiviral properties against canine adenovirus type 2 (CAV-2, canine coronavirus (CCoV, canine distemper virus (CDV, canine parvovirus type 2 (CPV-2, equine arteritis virus (EAV, equine influenza virus (EIV, feline calicivirus (FCV and feline herpesvirus type 1 (FHV-1. The results showed that the peptide P34 exhibited antiviral activity against EAV and FHV-1. The peptide P34 inhibited the replication of EAV by 99.9% and FHV-1 by 94.4%. Virucidal activity was detected only against EAV. When P34 and EAV were incubated for 6 h at 37 °C the viral titer reduced from 10(4.5 TCID50 to 10(2.75 TCID50, showing a percent of inhibition of 98.6%. In conclusion, our results demonstrated that P34 inhibited EAV and FHV-1 replication in infected cell cultures and it showed virucidal activity against EAV. Since there is documented resistance to the current drugs used against herpesviruses and there is no treatment for equine viral arteritis, it is advisable to search for new antiviral compounds to overcome these infections.

  15. Antiviral Ability of Kalanchoe gracilis Leaf Extract against Enterovirus 71 and Coxsackievirus A16

    Directory of Open Access Journals (Sweden)

    Ching-Ying Wang

    2012-01-01

    Full Text Available Pandemic infection or reemergence of Enterovirus 71 (EV71 and coxsackievirus A16 (CVA16 occurs in tropical and subtropical regions, being associated with hand-foot-and-mouth disease, herpangina, aseptic meningitis, brain stem encephalitis, pulmonary edema, and paralysis. However, effective therapeutic drugs against EV71 and CVA16 are rare. Kalanchoe gracilis (L. DC is used for the treatment of injuries, pain, and inflammation. This study investigated antiviral effects of K. gracilis leaf extract on EV71 and CVA16 replications. HPLC analysis with a C-18 reverse phase column showed fingerprint profiles of K. gracilis leaf extract had 15 chromatographic peaks. UV/vis absorption spectra revealed peaks 5, 12, and 15 as ferulic acid, quercetin, and kaempferol, respectively. K. gracilis leaf extract showed little cytotoxicity, but exhibited concentration-dependent antiviral activities including cytopathic effect, plaque, and virus yield reductions. K. gracilis leaf extract was shown to be more potent in antiviral activity than ferulic acid, quercetin, and kaempferol, significantly inhibiting in vitro replication of EV71 (IC50=35.88 μg/mL and CVA16 (IC50=42.91 μg/mL. Moreover, K. gracilis leaf extract is a safe antienteroviral agent with the inactivation of viral 2A protease and reduction of IL-6 and RANTES expressions.

  16. The antiviral activity of arctigenin in traditional Chinese medicine on porcine circovirus type 2.

    Science.gov (United States)

    Chen, Jie; Li, Wentao; Jin, Erguang; He, Qigai; Yan, Weidong; Yang, Hanchun; Gong, Shiyu; Guo, Yi; Fu, Shulin; Chen, Xiabing; Ye, Shengqiang; Qian, Yunguo

    2016-06-01

    Arctigenin (ACT) is a phenylpropanoid dibenzylbutyrolactone lignan extracted from the traditional herb Arctium lappa L. (Compositae) with anti-viral and anti-inflammatory effects. Here, we investigated the antiviral activity of ACT found in traditional Chinese medicine on porcine circovirus type 2 (PCV2) in vitro and in vivo. Results showed that dosing of 15.6-62.5μg/mL ACT could significantly inhibit the PCV2 proliferation in PK-15 cells (P<0.01). Dosing of 62.5μg/mL ACT 0, 4 or 8h after challenge inoculation significantly inhibited the proliferation of 1MOI and 10MOI in PK-15 cells (P<0.01), and the inhibitory effect of ACT dosing 4h or 8h post-inoculation was greater than 0h after dosing (P<0.01). In vivo test with mice challenge against PCV2 infection demonstrated that intraperitoneal injection of 200μg/kg ACT significantly inhibited PCV2 proliferation in the lungs, spleens and inguinal lymph nodes, with an effect similar to ribavirin, demonstrating the effectiveness of ACT as an antiviral agent against PCV2 in vitro and in vivo. This compound, therefore, may have the potential to serve as a drug for protection of pigs against the infection of PCV2. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Antiviral Ability of Kalanchoe gracilis Leaf Extract against Enterovirus 71 and Coxsackievirus A16

    Science.gov (United States)

    Wang, Ching-Ying; Huang, Shun-Chueh; Zhang, Yongjun; Lai, Zhen-Rung; Kung, Szu-Hao; Chang, Yuan-Shiun; Lin, Cheng-Wen

    2012-01-01

    Pandemic infection or reemergence of Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) occurs in tropical and subtropical regions, being associated with hand-foot-and-mouth disease, herpangina, aseptic meningitis, brain stem encephalitis, pulmonary edema, and paralysis. However, effective therapeutic drugs against EV71 and CVA16 are rare. Kalanchoe gracilis (L.) DC is used for the treatment of injuries, pain, and inflammation. This study investigated antiviral effects of K. gracilis leaf extract on EV71 and CVA16 replications. HPLC analysis with a C-18 reverse phase column showed fingerprint profiles of K. gracilis leaf extract had 15 chromatographic peaks. UV/vis absorption spectra revealed peaks 5, 12, and 15 as ferulic acid, quercetin, and kaempferol, respectively. K. gracilis leaf extract showed little cytotoxicity, but exhibited concentration-dependent antiviral activities including cytopathic effect, plaque, and virus yield reductions. K. gracilis leaf extract was shown to be more potent in antiviral activity than ferulic acid, quercetin, and kaempferol, significantly inhibiting in vitro replication of EV71 (IC50 = 35.88 μg/mL) and CVA16 (IC50 = 42.91 μg/mL). Moreover, K. gracilis leaf extract is a safe antienteroviral agent with the inactivation of viral 2A protease and reduction of IL-6 and RANTES expressions. PMID:22666293

  18. Using high-throughput sequencing to leverage surveillance of genetic diversity and oseltamivir resistance: a pilot study during the 2009 influenza A(H1N1) pandemic.

    Science.gov (United States)

    Téllez-Sosa, Juan; Rodríguez, Mario Henry; Gómez-Barreto, Rosa E; Valdovinos-Torres, Humberto; Hidalgo, Ana Cecilia; Cruz-Hervert, Pablo; Luna, René Santos; Carrillo-Valenzo, Erik; Ramos, Celso; García-García, Lourdes; Martínez-Barnetche, Jesús

    2013-01-01

    Influenza viruses display a high mutation rate and complex evolutionary patterns. Next-generation sequencing (NGS) has been widely used for qualitative and semi-quantitative assessment of genetic diversity in complex biological samples. The "deep sequencing" approach, enabled by the enormous throughput of current NGS platforms, allows the identification of rare genetic viral variants in targeted genetic regions, but is usually limited to a small number of samples. We designed a proof-of-principle study to test whether redistributing sequencing throughput from a high depth-small sample number towards a low depth-large sample number approach is feasible and contributes to influenza epidemiological surveillance. Using 454-Roche sequencing, we sequenced at a rather low depth, a 307 bp amplicon of the neuraminidase gene of the Influenza A(H1N1) pandemic (A(H1N1)pdm) virus from cDNA amplicons pooled in 48 barcoded libraries obtained from nasal swab samples of infected patients (n  =  299) taken from May to November, 2009 pandemic period in Mexico. This approach revealed that during the transition from the first (May-July) to second wave (September-November) of the pandemic, the initial genetic variants were replaced by the N248D mutation in the NA gene, and enabled the establishment of temporal and geographic associations with genetic diversity and the identification of mutations associated with oseltamivir resistance. NGS sequencing of a short amplicon from the NA gene at low sequencing depth allowed genetic screening of a large number of samples, providing insights to viral genetic diversity dynamics and the identification of genetic variants associated with oseltamivir resistance. Further research is needed to explain the observed replacement of the genetic variants seen during the second wave. As sequencing throughput rises and library multiplexing and automation improves, we foresee that the approach presented here can be scaled up for global genetic

  19. Contribution of autophagy to antiviral immunity.

    Science.gov (United States)

    Rey-Jurado, Emma; Riedel, Claudia A; González, Pablo A; Bueno, Susan M; Kalergis, Alexis M

    2015-11-14

    Although identified in the 1960's, interest in autophagy has significantly increased in the past decade with notable research efforts oriented at understanding as to how this multi-protein complex operates and is regulated. Autophagy is commonly defined as a "self-eating" process evolved by eukaryotic cells to recycle senescent organelles and expired proteins, which is significantly increased during cellular stress responses. In addition, autophagy can also play important roles during human diseases, such as cancer, neurodegenerative and autoimmune disorders. Furthermore, novel findings suggest that autophagy contributes to the host defense against microbial infections. In this article, we review the role of macroautophagy in antiviral immune responses and discuss molecular mechanisms evolved by viral pathogens to evade this process. A role for autophagy as an effector mechanism used both, by innate and adaptive immunity is also discussed. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  20. Mouse models for dengue vaccines and antivirals.

    Science.gov (United States)

    Plummer, Emily M; Shresta, Sujan

    2014-08-01

    Dengue virus (DENV) has substantial global impact, with an estimated 390million people infected each year. In spite of this, there is currently no approved DENV-specific vaccine or antiviral. One reason for this is the difficulty involved with development of an adequate animal model. While non-human primates support viral replication, they do not exhibit signs of clinical disease. A mouse model is an ideal alternative; however, wild-type mice are resistant to DENV-induced disease. Infection of interferon receptor-deficient mice results in disease that recapitulates key features of severe dengue disease in humans. For the development of vaccines, interferon receptor-deficient mice provide a stringent model for testing vaccine-induced immune components from vaccinated wild-type mice. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. RNAi: antiviral therapy against dengue virus.

    Science.gov (United States)

    Idrees, Sobia; Ashfaq, Usman A

    2013-03-01

    Dengue virus infection has become a global threat affecting around 100 countries in the world. Currently, there is no licensed antiviral agent available against dengue. Thus, there is a strong need to develop therapeutic strategies that can tackle this life threatening disease. RNA interference is an important and effective gene silencing process which degrades targeted RNA by a sequence specific process. Several studies have been conducted during the last decade to evaluate the efficiency of siRNA in inhibiting dengue virus replication. This review summarizes siRNAs as a therapeutic approach against dengue virus serotypes and concludes that siRNAs against virus and host genes can be next generation treatment of dengue virus infection.

  2. Cherry Valley Ducks Mitochondrial Antiviral-Signaling Protein-Mediated Signaling Pathway and Antiviral Activity Research.

    Science.gov (United States)

    Li, Ning; Hong, Tianqi; Li, Rong; Wang, Yao; Guo, Mengjiao; Cao, Zongxi; Cai, Yumei; Liu, Sidang; Chai, Tongjie; Wei, Liangmeng

    2016-01-01

    Mitochondrial antiviral-signaling protein (MAVS), an adaptor protein of retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs)-mediated signal pathway, is involved in innate immunity. In this study, Cherry Valley duck MAVS (duMAVS) was cloned from the spleen and analyzed. duMAVS was determined to have a caspase activation and recruitment domain at N-terminal, followed by a proline-rich domain and a transmembrane domain at C-terminal. Quantitative real-time PCR indicated that duMAVS was expressed in all tissues tested across a broad expression spectrum. The expression of duMAVS was significantly upregulated after infection with duck Tembusu virus (DTMUV). Overexpression of duMAVS could drive the activation of interferon (IFN)-β, nuclear factor-κB, interferon regulatory factor 7, and many downstream factors (such as Mx, PKR, OAS, and IL-8) in duck embryo fibroblast cells. What is more, RNA interference further confirmed that duMAVS was an important adaptor for IFN-β activation. The antiviral assay showed that duMAVS could suppress the various viral replications (DTMUV, novel reovirus, and duck plague virus) at early stages of infection. Overall, these results showed that the main signal pathway mediated by duMAVS and it had a broad-spectrum antiviral ability. This research will be helpful to better understanding the innate immune system of ducks.

  3. Innate and intrinsic antiviral immunity in skin.

    Science.gov (United States)

    Kawamura, Tatsuyoshi; Ogawa, Youichi; Aoki, Rui; Shimada, Shinji

    2014-09-01

    As the body's most exposed interface with the environment, the skin is constantly challenged by potentially pathogenic microbes, including viruses. To sense the invading viruses, various types of cells resident in the skin express many different pattern-recognition receptors (PRRs) such as C-type lectin receptors (CLRs), Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and cytosolic DNA sensors, that can detect the pathogen-associated molecular patterns (PAMPs) of the viruses. The detection of viral PAMPs initiates two major innate immune signaling cascades: the first involves the activation of the downstream transcription factors, such as interferon regulatory factors (IRFs), nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1), which cooperate to induce the transcription of type I interferons and pro-inflammatory cytokines. The second signaling pathway involves the caspase-1-mediated processing of IL-1β and IL-18 through the formation of an inflammasome complex. Cutaneous innate immunity including the production of the innate cytokines constitutes the first line of host defence that limits the virus dissemination from the skin, and also plays an important role in the activation of adaptive immune response, which represents the second line of defence. More recently, the third immunity "intrinsic immunity" has emerged, that provides an immediate and direct antiviral defense mediated by host intrinsic restriction factors. This review focuses on the recent advances regarding the antiviral immune systems, highlighting the innate and intrinsic immunity against the viral infections in the skin, and describes how viral components are recognized by cutaneous immune systems. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  4. Prophylactic antiviral therapy in allogeneic hematopoietic stem cell transplantation in hepatitis B virus patients.

    Science.gov (United States)

    Liao, Ya-Ping; Jiang, Jia-Lu; Zou, Wai-Yi; Xu, Duo-Rong; Li, Juan

    2015-04-14

    To investigate the timing, safety and efficacy of prophylactic antiviral therapy in patients with hepatitis B virus (HBV) infection undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This prospective study recruited a total of 57 patients diagnosed with malignant hematological diseases and HBV infection at the First Affiliated Hospital of Sun Yat-sen University between 2006 and 2013. The patients were classified as hepatitis B surface antigen (HBsAg)-positive or HBsAg-negative/ antiHBc-positive. Patients were treated with chemotherapy followed by antiviral therapy with nucleoside analogues. Patients underwent allo-HSCT when serum HBV DNA was antiviral therapy was continued for 1 year after the discontinuation of immunosuppressive therapy. A total of 105 patients who underwent allo-HSCT and had no HBV infection were recruited as controls. The three groups were compared for incidence of graft-vs-host disease (GVHD), drug-induced liver injury, hepatic veno-occlusive disease, death and survival time. A total of 29 of the 41 subjects with chronic GVHD exhibited extensive involvement and 12 exhibited focal involvement. Ten of the 13 subjects with chronic GVHD in the HBsAg(-)/hepatitis B core antibody(+) group exhibited extensive involvement and 3 exhibited focal involvement. Five of the 10 subjects with chronic GVHD in the HBsAg(+) group exhibited extensive involvement and 5 exhibited focal involvement. The non HBV-infected group did not differ significantly from the HBsAg-negative/antiHBc-positive and the HBsAg-positive groups which were treated with nucleoside analogues in the incidence of graft-vs-host disease (acute GVHD; 37.1%, 46.9% and 40%, respectively; P = 0.614; chronic GVHD; 39%, 40.6% and 40%, respectively; P = 0.98), drug-induced liver injury (25.7%, 18.7% and 28%, respectively; P = 0.7), death (37.1%, 40.6% and 52%, respectively; P = 0.4) and survival times (P = 0.516). One patient developed HBV reactivation (HBsAg-positivity) due to

  5. Molecular Sleds and More: Novel Antiviral Agents via Single-Molecule Biology (441st Brookhaven Lecture)

    Energy Technology Data Exchange (ETDEWEB)

    Mangel, Wally (Ph.D., Biology Department)

    2008-10-15

    Vaccines are effective against viruses such as polio and measles, but vaccines against other important viruses, such as HIV and flu viruses, may be impossible to obtain. These viruses change their genetic makeup each time they replicate so that the immune system cannot recognize all their variations. Hence it is important to develop new antiviral agents that inhibit virus replication. During this lecture, Dr. Mangel will discuss his group's work with a model system, the human adenovirus, which causes, among other ailments, pink eye, blindness and obesity. Mangel's team has developed a promising drug candidate that works by inihibiting adenovirus proteinase, an enzyme necessary for viral replication.

  6. Identification of a novel multiple kinase inhibitor with potent antiviral activity against influenza virus by reducing viral polymerase activity

    Energy Technology Data Exchange (ETDEWEB)

    Sasaki, Yutaka; Kakisaka, Michinori; Chutiwitoonchai, Nopporn [Viral Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan); Tajima, Shigeru [Department of Virology I, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo 162-8640 (Japan); Hikono, Hirokazu; Saito, Takehiko [Influenza and Prion Disease Research Center, National Institute of Animal Health, National Agriculture and Food Research Organization (NARO), 3-1-5 Kannondai, Tsukuba, Ibaraki 305-0856 (Japan); Aida, Yoko, E-mail: aida@riken.jp [Viral Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)

    2014-07-18

    Highlights: • Screening of 50,000 compounds and subsequent lead optimization identified WV970. • WV970 has antiviral effects against influenza A, B and highly pathogenic viral strains. • WV970 inhibits viral genome replication and transcription. • A target database search suggests that WV970 may bind to a number of kinases. • KINOMEscan screening revealed that WV970 has inhibitory effects on 15 kinases. - Abstract: Neuraminidase inhibitors are the only currently available influenza treatment, although resistant viruses to these drugs have already been reported. Thus, new antiviral drugs with novel mechanisms of action are urgently required. In this study, we identified a novel antiviral compound, WV970, through cell-based screening of a 50,000 compound library and subsequent lead optimization. This compound exhibited potent antiviral activity with nanomolar IC{sub 50} values against both influenza A and B viruses but not non-influenza RNA viruses. Time-of-addition and indirect immunofluorescence assays indicated that WV970 acted at an early stage of the influenza life cycle, but likely after nuclear entry of viral ribonucleoprotein (vRNP). Further analyses of viral RNA expression and viral polymerase activity indicated that WV970 inhibited vRNP-mediated viral genome replication and transcription. Finally, structure-based virtual screening and comprehensive human kinome screening were used to demonstrate that WV970 acts as a multiple kinase inhibitor, many of which are associated with influenza virus replication. Collectively, these results strongly suggest that WV970 is a promising anti-influenza drug candidate and that several kinases associated with viral replication are promising drug targets.

  7. Antiviral effect of HPMPC (Cidofovir (R)), entrapped in cationic liposomes: In vitro study on MDBK cell and BHV-1 virus

    Czech Academy of Sciences Publication Activity Database

    Korvasová, Z.; Drašar, L.; Mašek, J.; Turánek Knotigová, P.; Kulich, P.; Matiašovic, J.; Kovařčík, K.; Bartheldyová, E.; Koudelka, Š.; Škrabalová, M.; Miller, A. D.; Holý, Antonín; Ledvina, Miroslav; Turánek, J.

    2012-01-01

    Roč. 160, č. 2 (2012), s. 330-338 ISSN 0168-3659 R&D Projects: GA ČR(CZ) GAP304/10/1951; GA AV ČR(CZ) KAN200520703; GA AV ČR KAN200100801 Institutional research plan: CEZ:AV0Z40550506 Keywords : cationic lipids * BHV-1 virus * Cidofovir * HPMC * antiviral drugs Subject RIV: CC - Organic Chemistry Impact factor: 7.633, year: 2012

  8. Detection of peramivir and laninamivir, new anti-influenza drugs, in sewage effluent and river waters in Japan.

    Directory of Open Access Journals (Sweden)

    Takashi Azuma

    Full Text Available This is the first report of the detection of two new anti-influenza drugs, peramivir (PER and laninamivir (LAN, in Japanese sewage effluent and river waters. Over about 1 year from October 2013 to July 2014, including the influenza prevalence season in January and February 2014, we monitored for five anti-influenza drugs-oseltamivir (OS, oseltamivir carboxylate (OC, zanamivir (ZAN, PER, and LAN-in river waters and in sewage effluent flowing into urban rivers of the Yodo River system in Japan. The dynamic profiles of these anti-influenza drugs were synchronized well with that of the numbers of influenza patients treated with the drugs. The highest levels in sewage effluents and river waters were, respectively, 82 and 41 ng/L (OS, 347 and 125 ng/L (OC, 110 and 35 ng/L (ZAN, 64 and 11 ng/L (PER, and 21 and 9 ng/L (LAN. However, application of ozone treatment before discharge from sewage treatment plants was effective in reducing the levels of these anti-influenza drugs in effluent. The effectiveness of the ozone treatment and the drug dependent difference in susceptibility against ozone were further evidenced by ozonation of a STP effluent in a batch reactor. These findings should help to promote further environmental risk assessment of the generation of drug-resistant influenza viruses in aquatic environments.

  9. 76 FR 20689 - Guidance for Industry on Influenza: Developing Drugs for Treatment and/or Prophylaxis; Availability

    Science.gov (United States)

    2011-04-13

    ... Drug Information, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New..., Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 22... authorizations of antiviral drugs for influenza. This guidance is being issued consistent with FDA's good...

  10. Development of Small-Molecule Antivirals for Ebola

    Czech Academy of Sciences Publication Activity Database

    Janeba, Zlatko

    2015-01-01

    Roč. 35, č. 6 (2015), s. 1175-1194 ISSN 0198-6325 Institutional support: RVO:61388963 Keywords : antiviral * filovirus * Ebola virus * Marburg virus * hemorrhagic fever Subject RIV: CC - Organic Chemistry Impact factor: 9.135, year: 2015

  11. Dendrimers in drug research

    DEFF Research Database (Denmark)

    Boas, Ulrik; Heegaard, Peter M. H.

    2004-01-01

    and in vivo cytotoxicity, as well as biopermeability, biostability and immunogenicity. The review deals with numerous applications of dendrimers as tools for efficient multivalent presentation of biological ligands in biospecific recognition, inhibition and targeting. Dendrimers may be used as drugs...... for antibacterial and antiviral treatment and have found use as antitumor agents. The review highlights the use of dendrimers as drug or gene delivery devices in e.g. anticancer therapy, and the design of different host-guest binding motifs directed towards medical applications is described. Other specific examples...

  12. Antiviral phenolics from the leaves of Cleistocalyx operculatus

    DEFF Research Database (Denmark)

    Ha, Thi Kim Quy; Dao, Trong Tuan; Nguyen, Ngoc Hieu

    2016-01-01

    different influenza viruses, including H1N1, H9N2, novel H1N1, and oseltamivir-resistant novel H1N1 (H274Y mutation) expressed in HEK293 cells (IC50 values ranging from 5.07 ± 0.94 μM to 9.34 ± 2.52 μM, respectively). Kinetic experiments revealed the non-competitive inhibitory mode of both compounds 6 and 8....... Furthermore, these flavonoids reduced the cytopathic effect of the H1N1 virus in MDCK cells. The present study suggests the potential of two flavonoids (6 and 8) as new lead compounds for the development of novel NA inhibitors in the future....

  13. Mushrooms as a source of substances with antiviral activity

    Directory of Open Access Journals (Sweden)

    Martyna Kandefer-Szerszeń

    2014-08-01

    Full Text Available Water extracts the fructifications of 56 species of fungi were examined as a source of antiviral substances with activity against VS and vaccinia viruses. Extracts from 16 fungal species exhibited the antiviral activity. Water extracts from Boletus edulis active against vaccinia virus and extract from Armillariella mellea active against VS virus are particularly worth nothing. Both of them in applied concentrations were not toxic in chick embryo fibroblasts tissue culture.

  14. Meeting report: 27th International conference on antiviral research, in Raleigh, NC, USA.

    Science.gov (United States)

    Vere Hodge, R Anthony

    2014-11-01

    The 27th International Conference on Antiviral Research (ICAR) was held in Raleigh, North Carolina, USA from May 12 to 16, 2014. This article summarizes the principal invited lectures. John Drach (Elion Award) described the early days of antiviral drugs and their novel modes of action. Piet Herdewijn (Holý Award) used evolutionary pressure to select DNA polymerases that accept nucleoside analogs. Replacing thymine by 5-chlorouracil led to the generation of a new form of Escherichia coli. Adrian Ray (Prusoff Award) demonstrated how prodrugs can markedly improve both the efficacy and safety of potential drugs. The keynote addresses, by David Margolis and Myron Cohen, tackled two emerging areas of HIV research, to find an HIV "cure" and to prevent HIV transmission, respectively. These topics were discussed further in other presentations - a cure seems to be a distant prospect but there are exciting developments for reducing HIV transmission. TDF-containing vaginal rings and GSK-744, as a long-lasting injection, offer great hope. There were three mini-symposia. Although therapy with TDF/FTC gives excellent control of HBV replication, there are only a few patients who achieve a functional cure. Myrcludex, an entry inhibitor, is active against both HBV and HDV. The recent progress with HBV replication in cell cultures has transformed the search for new antiviral compounds. The HBV capsid protein has been recognized as key player in HBV DNA synthesis. Unexpectedly, compounds which enhance capsid formation, markedly reduce HBV DNA synthesis. The development of BCX4430, which is active against Marburg and Ebola viruses, is of great current interest. Copyright © 2014 The Author. Published by Elsevier B.V. All rights reserved.

  15. Is there a place for drug combination strategies using clinical pharmacology attributes?--review of current trends in research.

    Science.gov (United States)

    Srinivas, Nuggehally R

    2009-09-01

    Drug discovery is the main flag ship of the pharmaceutical industry in order to ensure that innovations constantly occur in the identification and development of novel therapeutic options for the management of diseases. Recently, research trends that take advantage of the safety and efficacy of marketed products by combining such products with other agents to influence certain clinical pharmacology attribute(s) have emerged. The focus of the review is to evaluate ongoing research trends that have considered leveraging on certain clinical pharmacology attributes in the areas of viral infection (HIV and influenza) and oncology. Case studies discussed in this review include: a) the use of probenecid to block the organic anion renal transport of oseltamivir carboxylate (a key active metabolite of oseltamivir phosphate) to reduce the oral dose of oseltamivir phosphate; b) the use of rifampicin to induce the CYP2C19 enzyme and thereby, promote the formation of a potent active metabolite M8 (nelfinavir hydroxyl-t-butylamide) and achieve sustained blood levels to combat HIV infection along with ritonavir; c) the use of CYP3A4 inhibitors such as ketoconazole, cyclosporin A, ritonavir etc to overcome the extensive presystemic metabolism of docetaxel and enhance the oral bioavailability of docetaxel. Along with the case studies, several hurdles for drug development such as dose selection, frequency of dosing, and duration of the clinical studies, picking the right surrogate(s) for efficacy, evaluation of drug-drug interaction potential with other co-substrates have been discussed in line with the current day requirements for a sound clinical and regulatory strategy. In summary, based on the collated information, a pragmatic approach would render feasibility for a balanced therapy management using combined clinical pharmacology attributes of drugs.

  16. Natural Products as Source of Potential Dengue Antivirals

    Directory of Open Access Journals (Sweden)

    Róbson Ricardo Teixeira

    2014-06-01

    Full Text Available Dengue is a neglected disease responsible for 22,000 deaths each year in areas where it is endemic. To date, there is no clinically approved dengue vaccine or antiviral for human beings, even though there have been great efforts to accomplish these goals. Several approaches have been used in the search for dengue antivirals such as screening of compounds against dengue virus enzymes and structure-based computational discovery. During the last decades, researchers have turned their attention to nature, trying to identify compounds that can be used as dengue antivirals. Nature represents a vast reservoir of substances that can be explored with the aim of discovering new leads that can be either used directly as pharmaceuticals or can serve as lead structures that can be optimized towards the development of new antiviral agents against dengue. In this review we describe an assortment of natural products that have been reported as possessing dengue antiviral activity. The natural products are organized into classes of substances. When appropriate, structure-activity relationships are outlined. The biological assays used to assess antiviral activity are briefly described.

  17. Effects of Smoking on Pegylated Interferon alpha 2a and First Generation Protease Inhibitor-based Antiviral Therapy in Naïve Patients Infected with Hepatitis C Virus Genotype 1.

    Science.gov (United States)

    Zimmermann, Tim; Hueppe, Dietrich; Mauss, Stefan; Buggisch, Peter; Pfeiffer-Vornkahl, Heike; Grimm, Daniel; Galle, Peter R; Alshuth, Ulrich

    2016-03-01

    Smoking has multiple effects on factors influencing hepatitis C and antiviral therapy, including lipid metabolism, fibrosis, platelet count and adherence aspects. The aim of this analysis was to determine the impact of smoking on hepatitis C virus antiviral therapy. Data of two cohorts of an observational multicenter study including therapy-naïve patients infected with genotype 1 hepatitis C virus (HCV) treated with dual antiviral therapy (n=7,796) with pegylated interferon alpha 2a in combination with ribavirin, or triple antiviral therapy (n=1,122) containing telaprevir or boceprevir, were analysed. In the univariate matched pair analysis of dual antiviral therapy patients (n=584), smoking was significantly associated with lower sustained viral response rates (p=0.026, OR 0.69 CI: 0.50 - 0.96). The effect of smoking on sustained viral response remained significant (p=0.028, OR 0.67 CI: 0.47 - 0.96) in the multivariate analysis when adjusting for all other baseline parameters with a significant association in the univariate analysis, i.e. diabetes, fibrosis, body mass index, transaminases and baseline viral load. Under protease inhibitors the influence of smoking on virological response did not arise. Smoking has a negative impact on antiviral therapy in naïve patients infected with HCV genotype 1 independently of age, gender, history of drug use or alcoholic liver disease. The effects of smoking might be overcome by the new antiviral agents.

  18. T cell--associated immunoregulation and antiviral effect of oxymatrine in hydrodynamic injection HBV mouse model.

    Science.gov (United States)

    Sang, Xiuxiu; Wang, Ruilin; Han, Yanzhong; Zhang, Cong'en; Shen, Honghui; Yang, Zhirui; Xiong, Yin; Liu, Huimin; Liu, Shijing; Li, Ruisheng; Yang, Ruichuang; Wang, Jiabo; Wang, Xuejun; Bai, Zhaofang; Xiao, Xiaohe

    2017-05-01

    Although oxymatrine (OMT) has been shown to directly inhibit the replication of hepatitis B virus (HBV) in vitro , limited research has been done with this drug in vivo . In the present study, the antiviral effect of OMT was investigated in an immunocompetent mouse model of chronic HBV infection. The infection was achieved by tail vein injection of a large volume of DNA solution. OMT (2.2, 6.7 and 20 mg/kg) was administered by daily intraperitoneal injection for 6 weeks. The efficacy of OMT was evaluated by the levels of HBV DNA, hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and hepatitis B core antigen (HBcAg). The immunoregulatory activity of OMT was evaluated by serum ELISA and flow cytometry. Results shows that OMT at 20 mg/kg inhibited HBV replication, and it was more efficient than entecavir (ETV) in the elimination of serum HBsAg and intrahepatic HBcAg. In addition, OMT accelerated the production of interferon- γ (IFN- γ ) in a dose-dependent manner in CD4 + T cells. Our findings demonstrate the beneficial effects of OMT on the enhancement of immunological function and in the control of HBV antigens. The findings suggest this drug to be a good antiviral therapeutic candidate for the treatment of HBV infection.

  19. Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism

    Science.gov (United States)

    Cagno, Valeria; Andreozzi, Patrizia; D'Alicarnasso, Marco; Jacob Silva, Paulo; Mueller, Marie; Galloux, Marie; Le Goffic, Ronan; Jones, Samuel T.; Vallino, Marta; Hodek, Jan; Weber, Jan; Sen, Soumyo; Janeček, Emma-Rose; Bekdemir, Ahmet; Sanavio, Barbara; Martinelli, Chiara; Donalisio, Manuela; Rameix Welti, Marie-Anne; Eleouet, Jean-Francois; Han, Yanxiao; Kaiser, Laurent; Vukovic, Lela; Tapparel, Caroline; Král, Petr; Krol, Silke; Lembo, David; Stellacci, Francesco

    2018-02-01

    Viral infections kill millions yearly. Available antiviral drugs are virus-specific and active against a limited panel of human pathogens. There are broad-spectrum substances that prevent the first step of virus-cell interaction by mimicking heparan sulfate proteoglycans (HSPG), the highly conserved target of viral attachment ligands (VALs). The reversible binding mechanism prevents their use as a drug, because, upon dilution, the inhibition is lost. Known VALs are made of closely packed repeating units, but the aforementioned substances are able to bind only a few of them. We designed antiviral nanoparticles with long and flexible linkers mimicking HSPG, allowing for effective viral association with a binding that we simulate to be strong and multivalent to the VAL repeating units, generating forces (~190 pN) that eventually lead to irreversible viral deformation. Virucidal assays, electron microscopy images, and molecular dynamics simulations support the proposed mechanism. These particles show no cytotoxicity, and in vitro nanomolar irreversible activity against herpes simplex virus (HSV), human papilloma virus, respiratory syncytial virus (RSV), dengue and lenti virus. They are active ex vivo in human cervicovaginal histocultures infected by HSV-2 and in vivo in mice infected with RSV.

  20. Effectiveness of topical corticosteroids in addition to antiviral therapy in the management of recurrent herpes labialis: a systematic review and meta-analysis.

    Science.gov (United States)

    Arain, Nasira; Paravastu, Sharath C V; Arain, Mubashir A

    2015-02-21

    Recurrent herpes labialis (RHL) is one of the most common viral infections worldwide. The available treatments have limited efficacy in preventing the recurrence of ulcerative lesions and reducing the duration of illness. The objective of this review was to identify the effectiveness of topical corticosteroids in addition to antiviral therapy in the treatment of RHL infection. A systematic review of randomized clinical trials comparing the efficacy of combined therapy (topical corticosteroids with antiviral) with placebo or antiviral alone in the management of RHL was conducted. MEDLINE, EMBASE, CINAHL, Web of Science, the Cochrane library, and Google Scholar databases were searched. We used RevMan software to conduct the meta-analysis. A fixed-effects model was used for mild to moderate heterogeneity, whereas a random-effects model was used for significant heterogeneity. Heterogeneity among trials was established using I(2) and chi-square test for heterogeneity. Four studies that fulfilled the selection criteria were included in this review. The total number of participants across included studies was 1,891 (range, 29 to 1,443). The antiviral drugs used were acyclovir, famciclovir, and valacyclovir. Corticosteroids used were 1% hydrocortisone and 0.05% fluocinonide. Pooled results showed that patients receiving combined therapy had a significantly lower recurrence rate of ulcerative lesions compared to those in both the placebo group (OR, 0.50; 95% CI, 0.39-0.66; P antiviral treatment alone group (OR, 0.73, 95% CI, 0.58-0.92; P = .007). The healing time was also significantly shorter in combined therapy in comparison to placebo (P therapy and antiviral alone. The adverse reactions in combined therapy were not significantly different than the placebo group (OR, 1.09; 95% C, 0.75-1.59; P = .85). Treatment with combined therapy is safe and more effective than placebo or antiviral alone for preventing the recurrence of ulcerative lesions in RHL infection.

  1. Antiviral activity of glycyrrhizin against hepatitis C virus in vitro.

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    Yoshihiro Matsumoto

    Full Text Available Glycyrrhizin (GL has been used in Japan to treat patients with chronic viral hepatitis, as an anti-inflammatory drug to reduce serum alanine aminotransferase levels. GL is also known to exhibit various biological activities, including anti-viral effects, but the anti-hepatitis C virus (HCV effect of GL remains to be clarified. In this study, we demonstrated that GL treatment of HCV-infected Huh7 cells caused a reduction of infectious HCV production using cell culture-produced HCV (HCVcc. To determine the target step in the HCV lifecycle of GL, we used HCV pseudoparticles (HCVpp, replicon, and HCVcc systems. Significant suppressions of viral entry and replication steps were not observed. Interestingly, extracellular infectivity was decreased, and intracellular infectivity was increased. By immunofluorescence and electron microscopic analysis of GL treated cells, HCV core antigens and electron-dense particles had accumulated on endoplasmic reticulum attached to lipid droplet (LD, respectively, which is thought to act as platforms for HCV assembly. Furthermore, the amount of HCV core antigen in LD fraction increased. Taken together, these results suggest that GL inhibits release of infectious HCV particles. GL is known to have an inhibitory effect on phospholipase A2 (PLA2. We found that group 1B PLA2 (PLA2G1B inhibitor also decreased HCV release, suggesting that suppression of virus release by GL treatment may be due to its inhibitory effect on PLA2G1B. Finally, we demonstrated that combination treatment with GL augmented IFN-induced reduction of virus in the HCVcc system. GL is identified as a novel anti-HCV agent that targets infectious virus particle release.

  2. Using high-throughput sequencing to leverage surveillance of genetic diversity and oseltamivir resistance: a pilot study during the 2009 influenza A(H1N1 pandemic.

    Directory of Open Access Journals (Sweden)

    Juan Téllez-Sosa

    Full Text Available BACKGROUND: Influenza viruses display a high mutation rate and complex evolutionary patterns. Next-generation sequencing (NGS has been widely used for qualitative and semi-quantitative assessment of genetic diversity in complex biological samples. The "deep sequencing" approach, enabled by the enormous throughput of current NGS platforms, allows the identification of rare genetic viral variants in targeted genetic regions, but is usually limited to a small number of samples. METHODOLOGY AND PRINCIPAL FINDINGS: We designed a proof-of-principle study to test whether redistributing sequencing throughput from a high depth-small sample number towards a low depth-large sample number approach is feasible and contributes to influenza epidemiological surveillance. Using 454-Roche sequencing, we sequenced at a rather low depth, a 307 bp amplicon of the neuraminidase gene of the Influenza A(H1N1 pandemic (A(H1N1pdm virus from cDNA amplicons pooled in 48 barcoded libraries obtained from nasal swab samples of infected patients (n  =  299 taken from May to November, 2009 pandemic period in Mexico. This approach revealed that during the transition from the first (May-July to second wave (September-November of the pandemic, the initial genetic variants were replaced by the N248D mutation in the NA gene, and enabled the establishment of temporal and geographic associations with genetic diversity and the identification of mutations associated with oseltamivir resistance. CONCLUSIONS: NGS sequencing of a short amplicon from the NA gene at low sequencing depth allowed genetic screening of a large number of samples, providing insights to viral genetic diversity dynamics and the identification of genetic variants associated with oseltamivir resistance. Further research is needed to explain the observed replacement of the genetic variants seen during the second wave. As sequencing throughput rises and library multiplexing and automation improves, we foresee that

  3. High antiviral effects of hibiscus tea extract on the H5 subtypes of low and highly pathogenic avian influenza viruses.

    Science.gov (United States)

    Baatartsogt, Tugsbaatar; Bui, Vuong N; Trinh, Dai Q; Yamaguchi, Emi; Gronsang, Dulyatad; Thampaisarn, Rapeewan; Ogawa, Haruko; Imai, Kunitoshi

    2016-10-01

    Viral neuraminidase inhibitors are widely used as synthetic anti-influenza drugs for the prevention and treatment of influenza. However, drug-resistant influenza A virus variants, including H5N1 highly pathogenic avian influenza viruses (HPAIVs), have been reported. Therefore, the discovery of novel and effective antiviral agents is warranted. We screened the antiviral effects of 11 herbal tea extracts (hibiscus, black tea, tencha, rosehip tea, burdock tea, green tea, jasmine tea, ginger tea, lavender tea, rose tea and oak tea) against the H5N1 HPAIV in vitro. Among the tested extracts, only the hibiscus extract and its fractionated extract (frHibis) highly and rapidly reduced the titers of all H5 HPAIVs and low pathogenic AIVs (LPAIVs) used in the pre-treatment tests of Madin-Darby canine kidney (MDCK) cells that were inoculated with a mixture of the virus and the extract. Immunogold electron microscopy showed that anti-H5 monoclonal antibodies could not bind to the deformed H5 virus particles pretreated with frHibis. In post-treatment tests of MDCK cells cultured in the presence of frHibis after infection with H5N1 HPAIV, the frHibis inhibited viral replication and the expression of viral antigens and genes. Among the plants tested, hibiscus showed the most prominent antiviral effects against both H5 HPAIV and LPAIV.

  4. Response to antiviral therapy in haematopoietic stem cell transplant recipients with cytomegalovirus (CMV) reactivation according to the donor CMV serological status.

    Science.gov (United States)

    Servais, S; Dumontier, N; Biard, L; Schnepf, N; Resche-Rigon, M; Peffault de Latour, R; Scieux, C; Robin, M; Meunier, M; Xhaard, A; Sicre de Fontbrune, F; Le Goff, J; Socié, G; Simon, F; Mazeron, M-C

    2016-03-01

    Pre-emptive antiviral treatment efficiently prevents occurrence of cytomegalovirus (CMV) disease in allogeneic stem cell transplant recipients. However, successive treatment courses can be necessary. The current study was aimed at determining factors that could influence the response to antiviral treatment, in particular the donor CMV serostatus. A total of 147 consecutive CMV-seropositive recipients (R+) were included and prospectively monitored for 6 months after transplantation. Reactivation of CMV occurred in 111 patients, 61 of 78 with a CMV-positive donor (D+) and in 50 of 69 with a CMV-negative donor (D-) (p 0.45). Baseline viral loads and initial viral doubling times did not differ between D+/R+ and D-/R+. Fifteen D+/R+ and four D-/R+ had self-resolving CMV infections. A total of 92 patients received antiviral treatment and 81 (88%) had a significant decrease in CMV load under therapy. Repeated CMV episodes were observed in 67% of those and were significantly more frequent in D-/R+ than in D+/R+ (p antivirals were found in two D-/R+. Donor CMV serostatus influenced neither CMV reactivation occurrence nor the kinetics of CMV DNA load in the early phase of CMV replication but had a significant impact on response to antiviral therapy. Virological drug-resistance remained rare. Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  5. Gestión del riesgo en la transferencia de procesos productivos: Aplicación a la fabricación de comprimidos de oseltamivir en la pandemia de gripe A Risk management in the transfer of manufacturing processes: Application to the manufacturing of oseltamivir tablets in the swine flu pandemic

    OpenAIRE

    A. Juberías Sánchez; A. Zamanillo Sainz; JI. Cabrera Merino; M. Verón Moros; MªL. Urquía Grande; MªL. Gonzalo Salado

    2011-01-01

    Introducción: La gestión de riesgos aplicada a la industria farmacéutica, a través de su identificación, valoración y control, es una herramienta útil para garantizar la calidad del medicamento. La declaración por la Organización Mundial de la Salud en el año 2.009, de la pandemia provocada por el virus de la influenza H1N1, origina la necesidad de transformar en medicamento parte de las reservas estratégicas de fosfato de oseltamivir, pertenecientes al Ministerio de Sanidad y Política Social...

  6. Direct-Acting Antivirals for the Treatment of Chronic Hepatitis C: Open Issues and Future Perspectives

    Directory of Open Access Journals (Sweden)

    Hee Bok Chae

    2013-01-01

    Full Text Available Currently, two direct-acting antivirals (DAAs show well-established efficacy against hepatitis C virus (HCV, namely, first-wave protease inhibitors telaprevir and boceprevir. Most clinical trials have examined DAAs in combination with standard of care (SOC regimens. Future therapeutic drugs were divided into three categories. They are second-wave protease inhibitors, second-generation protease inhibitors, and polymerase inhibitors. Second-wave protease inhibitors are more improved form and can be administered once a day. Oral drug combinations can be favored because interferon (IFN not only has to be given as intradermal injection, but also can cause several serious side effects. Combination of drugs with different mechanisms shows a good sustained virological response (SVR. But several mutations are associated with viral resistance to DAAs. Therefore, genotypic resistance data may provide insights into strategies aimed at maximizing SVR rates and minimizing resistance. Combined drug regimens are necessary to prevent the emergence of drug-resistant HCV. Many promising DAA candidates have been identified. Of these, a triple regimen containing sofosbuvir shows promise, and treatment with daclatasvir plus asunaprevir yields a high SVR rate (95%. Oral drug combinations will be standard of care in the near future.

  7. Modeling Viral Infectious Diseases and Development of Antiviral Therapies Using Human Induced Pluripotent Stem Cell-Derived Systems

    Directory of Open Access Journals (Sweden)

    Marta Trevisan

    2015-07-01

    Full Text Available The recent biotechnology breakthrough of cell reprogramming and generation of induced pluripotent stem cells (iPSCs, which has revolutionized the approaches to study the mechanisms of human diseases and to test new drugs, can be exploited to generate patient-specific models for the investigation of host–pathogen interactions and to develop new antimicrobial and antiviral therapies. Applications of iPSC technology to the study of viral infections in humans have included in vitro modeling of viral infections of neural, liver, and cardiac cells; modeling of human genetic susceptibility to severe viral infectious diseases, such as encephalitis and severe influenza; genetic engineering and genome editing of patient-specific iPSC-derived cells to confer antiviral resistance.

  8. Metabolic syndrome in chronic hepatitis C infection: does it still matter in the era of directly acting antiviral therapy?

    Directory of Open Access Journals (Sweden)

    Lim TR

    2014-12-01

    Full Text Available TR Lim Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, University of Birmingham and Liver and Hepatobiliary Unit, Queen Elizabeth Hospital Birmingham, UK Abstract: Metabolic syndrome is prevalent in patients with hepatitis C virus (HCV infection. Given the pandemic spread of HCV infection and metabolic syndrome, the burden of their interaction is a major public health issue. The presence of metabolic syndrome accelerates the progression of liver disease in patients with HCV infection. New drug development in HCV has seen an unprecedented rise in the last year, which resulted in better efficacy, better tolerance, and a shorter treatment duration. This review describes the underlying mechanisms and clinical effects of metabolic syndrome in HCV infection, as well as their importance in the era of new directly acting antiviral therapy. Keywords: HCV, genotype 3, metabolic syndrome, steatosis, directly acting antiviral agents

  9. Herpes simplex virus-1 entrapped in Candida albicans biofilm displays decreased sensitivity to antivirals and UVA1 laser treatment

    Directory of Open Access Journals (Sweden)

    Cristian Ascione

    2017-11-01

    Full Text Available Abstract Background Recently, we published data suggesting a mutualistic relationship between HSV-1 and Candida. albicans; in particular: (a HSV-1 infected macrophages are inhibited in their anti-Candida effector function and (b Candida biofilm protects HSV-1 from inactivation. The present in vitro study is aimed at testing the effects of Candida biofilm on HSV-1 sensitivity to pharmacological and physical stress, such as antiviral drugs (acyclovir and foscarnet and laser UVA1 irradiation. We also investigated whether fungus growth pattern, either sessile or planktonic, influences HSV-1 sensitivity to antivirals. Methods Mature Candida biofilms were exposed to HSV-1 and then irradiated with laser light (UVA1, 355 λ. In another set of experiments, mature Candida biofilm were co-cultured with HSV-1 infected VERO cells in the presence of different concentrations of acyclovir or foscarnet. In both protocols, controls unexposed to laser or drugs were included. The viral yield of treated and untreated samples was evaluated by end-point titration. To evaluate whether this protective effect might occur in relation with a different growth pattern, HSV-1 infected cells were co-cultured with either sessile or planktonic forms of Candida and then assessed for susceptibility to antiviral drugs. Results UVA1 irradiation caused a 2 Log reduction of virus yield in the control cultures whereas the reduction was only 1 Log with Candida biofilm, regardless to the laser dose applied to the experimental samples (50 or 100 J/cm2. The presence of biofilm increased the IC90 from 18.4–25.6 J/cm2. Acyclovir caused a 2.3 Log reduction of virus yield in the control cultures whereas with Candida biofilm the reduction was only 0.5 Log; foscarnet determined a reduction of 1.4 Log in the controls and 0.2 Log in biofilm cultures. Consequently, the ICs50 for acyclovir and foscarnet increased by 4- and 12-folds, respectively, compared to controls. When HSV-1 was exposed to

  10. Herpes simplex virus-1 entrapped in Candida albicans biofilm displays decreased sensitivity to antivirals and UVA1 laser treatment.

    Science.gov (United States)

    Ascione, Cristian; Sala, Arianna; Mazaheri-Tehrani, Elham; Paulone, Simona; Palmieri, Beniamino; Blasi, Elisabetta; Cermelli, Claudio

    2017-11-14

    Recently, we published data suggesting a mutualistic relationship between HSV-1 and Candida. albicans; in particular: (a) HSV-1 infected macrophages are inhibited in their anti-Candida effector function and (b) Candida biofilm protects HSV-1 from inactivation. The present in vitro study is aimed at testing the effects of Candida biofilm on HSV-1 sensitivity to pharmacological and physical stress, such as antiviral drugs (acyclovir and foscarnet) and laser UVA1 irradiation. We also investigated whether fungus growth pattern, either sessile or planktonic, influences HSV-1 sensitivity to antivirals. Mature Candida biofilms were exposed to HSV-1 and then irradiated with laser light (UVA1, 355 λ). In another set of experiments, mature Candida biofilm were co-cultured with HSV-1 infected VERO cells in the presence of different concentrations of acyclovir or foscarnet. In both protocols, controls unexposed to laser or drugs were included. The viral yield of treated and untreated samples was evaluated by end-point titration. To evaluate whether this protective effect might occur in relation with a different growth pattern, HSV-1 infected cells were co-cultured with either sessile or planktonic forms of Candida and then assessed for susceptibility to antiviral drugs. UVA1 irradiation caused a 2 Log reduction of virus yield in the control cultures whereas the reduction was only 1 Log with Candida biofilm, regardless to the laser dose applied to the experimental samples (50 or 100 J/cm 2 ). The presence of biofilm increased the IC 90 from 18.4-25.6 J/cm 2 . Acyclovir caused a 2.3 Log reduction of virus yield in the control cultures whereas with Candida biofilm the reduction was only 0.5 Log; foscarnet determined a reduction of 1.4 Log in the controls and 0.2 Log in biofilm cultures. Consequently, the ICs 50 for acyclovir and foscarnet increased by 4- and 12-folds, respectively, compared to controls. When HSV-1 was exposed to either sessile or planktonic fungal cells, the

  11. Oseltamivir-resistant pandemic A(H1N1) 2009 influenza viruses detected through enhanced surveillance in the Netherlands, 2009-2010.

    NARCIS (Netherlands)

    Meijer, F.J.A.; Jonges, M.; Abbink, F.; Ang, W.; Beek, J.; Beersma, M.; Bloembergen, P.; Boucher, C.; Claas, E.; Donker, G; Gageldonk-Lafeber, R. van; Isken, L.; Jong, A. de; Kroes, A.; Leenders, S.; Lubben, M. van der; Mascini, E.; Niesters, B.; Oosterheert, J.J.; Osterhaus, A.; Riesmeijer, R.; Riezebos-Brilman, A.; Schutten, M.; Sebens, F.; Stelma, F.F.; Swaan, C.; Timen, A.; Veen, A.; Vries, E. de; Wierik, M. te; Koopmans, M.

    2011-01-01

    Enhanced surveillance of infections due to the pandemic A(H1N1) influenza virus, which included monitoring for antiviral resistance, was carried out in the Netherlands from late April 2009 through late May 2010. More than 1100 instances of infection with the pandemic A(H1N1) influenza virus from

  12. Antiviral responses of arthropod vectors: an update on recent advances.

    Science.gov (United States)

    Rückert, Claudia; Bell-Sakyi, Lesley; Fazakerley, John K; Fragkoudis, Rennos

    2014-01-01

    Arthropod vectors, such as mosquitoes, ticks, biting midges and sand flies, transmit many viruses that can cause outbreaks of disease in humans and animals around the world. Arthropod vector species are invading new areas due to globalisation and environmental changes, and contact between exotic animal species, humans and arthropod vectors is increasing, bringing with it the regular emergence of new arboviruses. For future strategies to control arbovirus transmission, it is important to improve our understanding of virus-vector interactions. In the last decade knowledge of arthropod antiviral immunity has increased rapidly. RNAi has been proposed as the most important antiviral response in mosquitoes and it is likely to be the most important antiviral response in all arthropods. However, other newly-discovered antiviral strategies such as melanisation and the link between RNAi and the JAK/STAT pathway via the cytokine Vago have been characterised in the last few years. This review aims to summarise the most important and most recent advances made in arthropod antiviral immunity.

  13. Antiviral Screening of Multiple Compounds against Ebola Virus

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    Stuart D. Dowall

    2016-10-01

    Full Text Available In light of the recent outbreak of Ebola virus (EBOV disease in West Africa, there have been renewed efforts to search for effective antiviral countermeasures. A range of compounds currently available with broad antimicrobial activity have been tested for activity against EBOV. Using live EBOV, eighteen candidate compounds were screened for antiviral activity in vitro. The compounds were selected on a rational basis because their mechanisms of action suggested that they had the potential to disrupt EBOV entry, replication or exit from cells or because they had displayed some antiviral activity against EBOV in previous tests. Nine compounds caused no reduction in viral replication despite cells remaining healthy, so they were excluded from further analysis (zidovudine; didanosine; stavudine; abacavir sulphate; entecavir; JB1a; Aimspro; celgosivir; and castanospermine. A second screen of the remaining compounds and the feasibility of appropriateness for in vivo testing removed six further compounds (ouabain; omeprazole; esomeprazole; Gleevec; D-LANA-14; and Tasigna. The three most promising compounds (17-DMAG; BGB324; and NCK-8 were further screened for in vivo activity in the guinea pig model of EBOV disease. Two of the compounds, BGB324 and NCK-8, showed some effect against lethal infection in vivo at the concentrations tested, which warrants further investigation. Further, these data add to the body of knowledge on the antiviral activities of multiple compounds against EBOV and indicate that the scientific community should invest more effort into the development of novel and specific antiviral compounds to treat Ebola virus disease.

  14. 3,7-Dideazaneplanocin: Synthesis and antiviral analysis.

    Science.gov (United States)

    Yin, Xue-Qiang; Schneller, Stewart W

    2017-12-01

    Objective To synthesize 3,7-dideazaneplanocin and evaluate its antiviral potential. Methods The target 3,7-dideazaneplanocin has been prepared in five steps from a readily available cyclopentenol. A thorough in vitro antiviral analysis was conducted versus both DNA and RNA viruses. Results A rational synthesis of 3,7-dideazaneplanocin was conceived and successfully pursued in such a way that it can be adapted to various analogs of 3,7-dideazaneplanocin. Using standard antiviral assays, no activity for 3,7-dideazaneplanocn was found. Conclusion Two structural features are necessary for adenine-based carbocyclic nucleosides (like neplanocin) for potential antiviral properties: (i) inhibition of S-adenosylhomocysteine hydrolase and/or (ii) C-5' activation via the mono-nucleotide. These two requisite adenine structural features to fit these criteria are not present in in the target 3,7-dideazaneplanocin: (i) an N-7 is necessary for inhibition of the hydrolase and the N-3 is claimed to be essential for phosphorylation at C-5'. Thus, it is not surprising that 3,7-dideazaneplaoncin lacked antiviral properties.

  15. Mechanisms of virus resistance and antiviral activity of snake venoms

    Directory of Open Access Journals (Sweden)

    JVR Rivero

    2011-01-01

    Full Text Available Viruses depend on cell metabolism for their own propagation. The need to foster an intimate relationship with the host has resulted in the development of various strategies designed to help virus escape from the defense mechanisms present in the host. Over millions of years, the unremitting battle between pathogens and their hosts has led to changes in evolution of the immune system. Snake venoms are biological resources that have antiviral activity, hence substances of significant pharmacological value. The biodiversity in Brazil with respect to snakes is one of the richest on the planet; nevertheless, studies on the antiviral activity of venom from Brazilian snakes are scarce. The antiviral properties of snake venom appear as new promising therapeutic alternative against the defense mechanisms developed by viruses. In the current study, scientific papers published in recent years on the antiviral activity of venom from various species of snakes were reviewed. The objective of this review is to discuss the mechanisms of resistance developed by viruses and the components of snake venoms that present antiviral activity, particularly, enzymes, amino acids, peptides and proteins.

  16. Bioprospecting of Red Sea Sponges for Novel Antiviral Pharmacophores

    KAUST Repository

    O'Rourke, Aubrie

    2015-05-01

    Natural products offer many possibilities for the treatment of disease. More than 70% of the Earth’s surface is ocean, and recent exploration and access has allowed for new additions to this catalog of natural treasures. The Central Red Sea off the coast of Saudi Arabia serves as a newly accessible location, which provides the opportunity to bioprospect marine sponges with the purpose of identifying novel antiviral scaffolds. Antivirals are underrepresented in present day clinical trials, as well as in the academic screens of marine natural product libraries. Here a high-throughput pipeline was initiated by prefacing the antiviral screen with an Image-based High-Content Screening (HCS) technique in order to identify candidates with antiviral potential. Prospective candidates were tested in a biochemical or cell-based assay for the ability to inhibit the NS3 protease of the West Nile Virus (WNV NS protease) as well as replication and reverse transcription of the Human Immunodeficiency Virus 1 (HIV-1). The analytical chemistry techniques of High-Performance Liquid Chromatograpy (HPLC), Liquid Chromatography-Mass Spectrometry (LC-MS), and Nuclear Magnetic Resonance (NMR) where used in order to identify the compounds responsible for the characteristic antiviral activity of the selected sponge fractions. We have identified a 3-alkyl pyridinium from Amphimedon chloros as the causative agent of the observed WNV NS3 protease inhibition in vitro. Additionally, we identified debromohymenialdisine, hymenialdisine, and oroidin from Stylissa carteri as prospective scaffolds capable of HIV-1 inhibition.

  17. Screening of Brazilian medicinal plants for antiviral activity against rotavirus.

    Science.gov (United States)

    Cecílio, Alzira Batista; de Faria, Déborah Behr; Oliveira, Pollyana de Carvalho; Caldas, Sérgio; de Oliveira, Dario Alves; Sobral, Marcos Eduardo Guerra; Duarte, Maria Gorette Resende; Moreira, Carolina Paula de Souza; Silva, Cláudia Gontijo; de Almeida, Vera Lúcia

    2012-06-14

    Brazilian medicinal plants traditionally used for the treatment of diarrhoea were investigated for their in vitro antiviral activity against the simian rotavirus SA11. The ethanolic crude extracts of plants collected in the cerrado of Minas Gerais, Brazil were submitted to phytochemical screening. The cytotoxicity of the extracts was inferred by cellular morphologic alterations. Antiviral activity was assessed by the ability of the extracts to inhibit the cytopathic effect (CPE) of rotavirus on the treated cells. RT-PCR was performed to confirm and/or confront antiviral assay data. The maximum non-toxic concentration ranged from 50 to 500 μg/mL. All extracts were toxic at a concentration of 5000 μg/mL but no extract showed cytotoxicity at 50 μg/mL. The species Byrsonima verbascifolia, Myracrodruon urundeuva, Eugenia dysenterica and Hymenaea courbaril exhibited the strongest in vitro activity against rotavirus. Their extracts prevented the formation of CPE, and RT-PCR analysis detected no amplification of genetic material from rotavirus. Tannins, flavonoids, saponins, coumarins and terpenes were the major classes of natural products found in the leaf extracts that showed antiviral activity. Among the species studied, Byrsonima verbascifolia, Eugenia dysenterica, Hymenaea courbaril and Myracrodruon urundeuva showed potential activity against rotavirus and are worthy of further study. The present study corroborates ethnopharmacological data as a valuable source in the selection of plants with antiviral activity and to some extent validates their traditional uses. Published by Elsevier Ireland Ltd.

  18. Recent developments in antiviral agents against enterovirus 71 infection.

    Science.gov (United States)

    Tan, Chee Wah; Lai, Jeffrey Kam Fatt; Sam, I-Ching; Chan, Yoke Fun

    2014-02-12

    Enterovirus 71 (EV-71) is the main etiological agent of hand, foot and mouth disease (HFMD). Recent EV-71 outbreaks in Asia-Pacific were not limited to mild HFMD, but were associated with severe neurological complications such as aseptic meningitis and brainstem encephalitis, which may lead to cardiopulmonary failure and death. The absence of licensed therapeutics for clinical use has intensified research into anti-EV-71 development. This review highlights the potential antiviral agents targeting EV-71 attachment, entry, uncoating, translation, polyprotein processing, virus-induced formation of membranous RNA replication complexes, and RNA-dependent RNA polymerase. The strategies for antiviral development include target-based synthetic compounds, anti-rhinovirus and poliovirus libraries screening, and natural compound libraries screening. Growing knowledge of the EV-71 life cycle will lead to successful development of antivirals. The continued effort to develop antiviral agents for treatment is crucial in the absence of a vaccine. The coupling of antivirals with an effective vaccine will accelerate eradication of the disease.

  19. Several hPepT1-transported drugs are substrates of the Escherichia coli proton-coupled oligopeptide transporter YdgR.

    Science.gov (United States)

    Prabhala, Bala K; Aduri, Nanda G; Iqbal, Mazhar; Rahman, Moazur; Gajhede, Michael; Hansen, Paul R; Mirza, Osman

    2017-06-01

    Proton-dependent oligopeptide transporters (POTs) are secondary active transporters found in all kingdoms of life. POTs utilize the proton electrochemical gradient for the uptake of nutrient dipeptides and tripeptides. The human POT hPepT1 is known to transport a number of drugs. As part of ongoing studies on substrate specificities of POTs from Escherichia coli, our aim in this study was to investigate whether bacterial POTs could also transport these drugs. For this, we selected the common orally administered drugs sulpiride, bestatin, valacyclovir, ampicillin and oseltamivir, that are all transported by hPepT1. The transport of these drugs was evaluated using the prototypical POT YdgR from E. coli. The transport studies were pursued through combining cell-based assays with liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis. These investigations revealed that YdgR from E. coli is able to transport five (sulpiride, bestatin, valacyclovir, ampicillin and oseltamivir) drugs. Furthermore, cells not overexpressing YdgR were also able to transport these drugs in a POT-like manner. Orthologues of YdgR are found in several species in the gut microbiome; hence, our findings could have implications for further understanding about the interaction between gut microbes and orally administered drugs. Copyright © 2017 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  20. Antiviral activity of stachyflin on influenza A viruses of different hemagglutinin subtypes.

    Science.gov (United States)

    Motohashi, Yurie; Igarashi, Manabu; Okamatsu, Masatoshi; Noshi, Takeshi; Sakoda, Yoshihiro; Yamamoto, Naoki; Ito, Kimihito; Yoshida, Ryu; Kida, Hiroshi

    2013-04-16

    The hemagglutinin (HA) of influenza viruses is a possible target for antiviral drugs because of its key roles in the initiation of infection. Although it was found that a natural compound, Stachyflin, inhibited the growth of H1 and H2 but not H3 influenza viruses in MDCK cells, inhibitory activity of the compound has not been assessed against H4-H16 influenza viruses and the precise mechanism of inhibition has not been clarified. Inhibitory activity of Stachyflin against H4-H16 influenza viruses, as well as H1-H3 viruses was examined in MDCK cells. To identify factors responsible for the susceptibility of the viruses to this compound, Stachyflin-resistant viruses were selected in MDCK cells and used for computer docking simulation. It was found that in addition to antiviral activity of Stachyflin against influenza viruses of H1 and H2 subtypes, it inhibited replication of viruses of H5 and H6 subtypes, as well as A(H1N1)pdm09 virus in MDCK cells. Stachyflin also inhibited the virus growth in the lungs of mice infected with A/WSN/1933 (H1N1) and A/chicken/Ibaraki/1/2005 (H5N2). Substitution of amino acid residues was found on the HA2 subunit of Stachyflin-resistant viruses. Docking simulation indicated that D37, K51, T107, and K121 are responsible for construction of the cavity for the binding of the compound. In addition, 3-dimensional structure of the cavity of the HA of Stachyflin-susceptible virus strains was different from that of insusceptible virus strains. Antiviral activity of Stachyflin was found against A(H1N1)pdm09, H5, and H6 viruses, and identified a potential binding pocket for Stachyflin on the HA. The present results should provide us with useful information for the development of HA inhibitors with more effective and broader spectrum.

  1. Antiviral activity of A771726, the active metabolite of leflunomide, against Junín virus.

    Science.gov (United States)

    Sepúlveda, Claudia S; García, Cybele C; Damonte, Elsa B

    2018-05-01

    The aim of this study was to investigate the effect of A771726, the active metabolite of leflunomide, (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad against the infection with Junín virus (JUNV), agent of Argentine hemorrhagic fever (AHF). The treatment with non-cytotoxic concentrations of A771726 of Vero and A549 cells infected with JUNV inhibited virus replication in a dose-dependent manner, as determined by virus yield reduction assay. The antiviral effectiveness of A771726 was not importantly affected by the multiplicity of infection and the virus strain. Moreover, the combination of A771726 and ribavirin had a significantly more potent antiviral activity than each single drug treatment. Mechanistic studies showed that the main action of A771726 is exerted before 6 h of JUNV infection. Accordingly, inhibition of viral RNA synthesis was detected in treated infected cells by real time RT-PCR. The exogenous addition of uridine or orotic acid produced a partial reversal of the inhibitory effect of A771726 on infective virus production whereas a total reversion was detected on JUNV RNA synthesis, probably by restoration of the enzymatic activity of dihydroorotate dehydrogenase (DHODH) and the intracellular pyrimidine pools. In conclusion, these results suggest that the antiviral target would be viral RNA synthesis through pyrimidine depletion, but any other effect of the compound on JUNV infection cannot be excluded. This study opens the possibility of the therapeutic application of a wide spectrum host-targeted compound alone or in combination with ribavirin to combat AHF as well as other human pathogenic arenaviruses. © 2018 Wiley Periodicals, Inc.

  2. Structural Basis for Suppression of a Host Antiviral Response by Influenza A Virus

    Energy Technology Data Exchange (ETDEWEB)

    Das,K.; Ma, L.; Xiao, R.; Radvansky, B.; Aramini, J.; Zhao, L.; Marklund, J.; Kuo, R.; Twu, K.; Arnold, E.

    2008-01-01

    Influenza A viruses are responsible for seasonal epidemics and high mortality pandemics. A major function of the viral NS1A protein, a virulence factor, is the inhibition of the production of IFN-{beta}{beta} mRNA and other antiviral mRNAs. The NS1A protein of the human influenza A/Udorn/72 (Ud) virus inhibits the production of these antiviral mRNAs by binding the cellular 30-kDa subunit of the cleavage and polyadenylation specificity factor (CPSF30), which is required for the 3' end processing of all cellular pre-mRNAs. Here we report the 1.95- Angstroms resolution X-ray crystal structure of the complex formed between the second and third zinc finger domain (F2F3) of CPSF30 and the C-terminal domain of the Ud NS1A protein. The complex is a tetramer, in which each of two F2F3 molecules wraps around two NS1A effector domains that interact with each other head-to-head. This structure identifies a CPSF30 binding pocket on NS1A comprised of amino acid residues that are highly conserved among human influenza A viruses. Single amino acid changes within this binding pocket eliminate CPSF30 binding, and a recombinant Ud virus expressing an NS1A protein with such a substitution is attenuated and does not inhibit IFN-{beta} pre-mRNA processing. This binding pocket is a potential target for antiviral drug development. The crystal structure also reveals that two amino acids outside of this pocket, F103 and M106, which are highly conserved (>99%) among influenza A viruses isolated from humans, participate in key hydrophobic interactions with F2F3 that stabilize the complex.

  3. Bleomycin has antiviral properties against drug-resistant HIV strains and sensitises virus to currently used antiviral agents.

    NARCIS (Netherlands)

    Georgiou, N.A.; Bruggen, T. van der; Healy, D.M.; Tienen, C. van; Bie, P. de; Oudshoorn, M.; Marx, J.J.M.; Asbeck, B.S. van

    2006-01-01

    In this study we performed phenotypic assays to assess involvement of the cancer chemotherapeutic agent bleomycin (BLM) in replication inhibition of mutant HIV-1 viral strains. Three clinically relevant mutant HIV variants, including one containing the Q151M mutation conferring multinucleoside

  4. Terapia antiviral para VIH-SIDA

    Directory of Open Access Journals (Sweden)

    Alicia Tarinas Reyes

    2000-12-01

    Full Text Available En los últimos años, muchos agentes antivirales nuevos han sido incorporados a la quimioterapéutica. En esta revisión se resumen tanto los fármacos establecidos de años atrás como los nuevos medicamentos desarrollados para el tratamiento de individuos infectados por VIH. El AZT fue el primero aprobado en marzo de 1987, le siguió el ddl (1991, ddC (1992, d4T (1994, 3TC (1995. Luego fue aprobado el primer inhibidor de proteasa, saquinavir en diciembre de 1995, seguido de ritonavir (1996, indinavir (1996, nelfinavir (1997; además de otros inhibidores de la reverso transcriptasa como nevirapine (1996, delavirdine (1997, efavirenz (1998, entre otros. En estos momentos se siguen buscando y desarrollando nuevas terapias alternativas para esta afección. En este trabajo se exponen algunas de las características de dichos medicamentos, como son: mecanismos de acción (sobre qué enzima actúa cada uno y cómo lo hacen, el ciclo viral, dosificación, incompatibilidades y reacciones adversas.During the last years many new antiviral agents have been incorporated to the chemotherapeutics. The pharmaceuticals established years ago as well as the new ones developed to treat HIV infected individuals are included in this review. The AZT was the first approved in March, 1987, followed by ddl (1991, ddc (1992, d4t (1994, and 3TC (1995. Later, the first protease inhibitor, saquinovir, was approved in December, 1995, followed by ritonavir (1996, indinavir (1996, and nelfinavir (1997; in addition to other inhibitors of the reverse transcriptase as neviparine (1996, delavirdine (1997, and efavirenz (1998, among others. At present new alternative therapies for this affection are being searched and developed. Some of the characteristics of these dugs, such as: action mechanisms (on which enzime each of them act and how they do it, viral cycle, dosage, incompatibilites and adverse reactions are dealt with in this paper.

  5. Sudden sensorineural hearing loss: Is antiviral treatment really necessary?

    Science.gov (United States)

    Övet, Gültekin; Alataş, Necat; Kocacan, Fatma Nur; Gürcüoğlu, Sermin Selver; Görgülü, Hakan; Güzelkara, Fatih; Övet, Habibe

    2015-01-01

    It was aimed to investigate the necessity of antiviral agents in the ISSHL treatment. In this study, the patients, diagnosed with sudden hearing loss and admitted in the first 7 days of hearing loss were divided into two groups; a combination therapy was administered to one of the groups, and famciclovir was administered to the other group as an antiviral treatment in addition to the combined therapy. Both groups were compared in terms of levels of recovery. No statistically significant difference was found in the recovery rates between the two groups (p=0.7). In this study, the additional antiviral treatment was found to have no effect on the remission rates in patients with ISSHL treated with combined therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Phytochemistry, cytotoxicity and antiviral activity of Eleusine indica (sambau)

    Science.gov (United States)

    Iberahim, Rashidah; Yaacob, Wan Ahmad; Ibrahim, Nazlina

    2015-09-01

    Goose grass also known as Eleusine indica (EI) is a local medicinal plant that displays antioxidant, antimicrobial and anticancer activities. The present study is to determine the phytochemical constituents, cytotoxicity and antiviral activities for both crude extract and fraction obtained from the plant. The crude extract contained more secondary metabolites compared to the hexane fraction as gauged using standard phytochemical tests. Cytotoxicity screening against Vero cells using MTT assay showed that the CC50 values for crude extract and hexane fraction were 2.07 and 5.62 mg/ml respectively. The antiviral activity towards Herpes Simplex Virus type 1 (HSV-1) was determined using plaque reduction assay. The selective indices (SI = CC50 / EC50) for both methanol extract and hexane fraction were 12.2 and 6.2 respectively. These results demonstrate that the extract prepared from E. indica possesses phytochemical compound that was non cytotoxic to the cell with potential antiviral activity.

  7. The Antiviral Effect of Baicalin on Enterovirus 71 In Vitro

    Directory of Open Access Journals (Sweden)

    Xiang Li

    2015-08-01

    Full Text Available Baicalin is a flavonoid compound extracted from Scutellaria roots that has been reported to possess antibacterial, anti-inflammatory, and antiviral activities. However, the antiviral effect of baicalin on enterovirus 71 (EV71 is still unknown. In this study, we found that baicalin showed inhibitory activity on EV71 infection and was independent of direct virucidal or prophylactic effect and inhibitory viral absorption. The expressions of EV71/3D mRNA and polymerase were significantly blocked by baicalin treatment at early stages of EV71 infection. In addition, baicalin could decrease the expressions of FasL and caspase-3, as well as inhibit the apoptosis of EV71-infected human embryonal rhabdomyosarcoma (RD cells. Altogether, these results indicate that baicalin exhibits potent antiviral effect on EV71 infection, probably through inhibiting EV71/3D polymerase expression and Fas/FasL signaling pathways.

  8. Resveratrol exhibits a strong cytotoxic activity in cultured cells and has an antiviral action against polyomavirus: potential clinical use

    Directory of Open Access Journals (Sweden)

    Galati Gaspare

    2009-07-01

    Full Text Available Abstract Background Resveratrol is a non flavonoid polyphenol compound present in many plants and fruits and, at especially high concentrations, in the grape berries of Vitis vinifera. This compound has a strong bioactivity and its cytoprotective action has been demonstrated, however at high concentrations the drug exhibits also an effective anti-proliferative action. We recently showed its ability to abolish the effects of oxidative stress in cultured cells. In this work we assayed the bioactivity of resveratrol as antiproliferative and antiviral drug in cultured fibroblasts. Studies by other Authors showed that this natural compound inhibits the proliferation of different viruses such as herpes simplex, varicella-zoster and influenza A. The results presented here show an evident toxic activity of the drug at high concentrations, on the other hand at sub-cytotoxic concentrations, resveratrol can effectively inhibit the synthesis of polyomavirus DNA. A possible interpretation is that, due to the damage caused by resveratrol to the plasma membrane, the transfer of the virus from the endoplasmic reticulum to the nucleus, may be hindered thus inhibiting the production of viral DNA. Methods The mouse fibroblast line 3T6 and the human tumor line HL60 were used throughout the work. Cell viability and vital cell count were assessed respectively, by the MTT assay and Trypan Blue staining. Cytotoxic properties and evaluation of viral DNA production by agarose gel electrophoresis were performed according to standard protocols. Results Our results show a clear dose dependent both cytotoxic and antiviral effect of resveratrol respectively at high and low concentrations. The cytotoxic action is exerted towards a stabilized cell-line (3T6 as well as a tumor-line (HL60. Furthermore the antiviral action is evident after the phase of virion entry, therefore data suggest that the drug acts during the synthesis of the viral progeny DNA. Conclusion Resveratrol is

  9. A Novel Iminosugar UV-12 with Activity against the Diverse Viruses Influenza and Dengue (Novel Iminosugar Antiviral for Influenza and Dengue).

    Science.gov (United States)

    Warfield, Kelly L; Plummer, Emily; Alonzi, Dominic S; Wolfe, Gary W; Sampath, Aruna; Nguyen, Tam; Butters, Terry D; Enterlein, Sven G; Stavale, Eric J; Shresta, Sujan; Ramstedt, Urban

    2015-05-13

    Iminosugars are capable of targeting the life cycles of multiple viruses by blocking host endoplasmic reticulum α-glucosidase enzymes that are required for competent replication of a variety of enveloped, glycosylated viruses. Iminosugars as a class are approved for use in humans with diseases such as diabetes and Gaucher's disease, providing evidence for safety of this class of compounds. The in vitro antiviral activity of iminosugars has been described in several publications with a subset of these demonstrating in vivo activity against flaviviruses, herpesviruses, retroviruses and filoviruses. Although there is compelling non-clinical in vivo evidence of antiviral efficacy, the efficacy of iminosugars as antivirals has yet to be demonstrated in humans. In the current study, we report a novel iminosugar, UV-12, which has efficacy against dengue and influenza in mouse models. UV-12 exhibits drug-like properties including oral bioavailability and good safety profile in mice and guinea pigs. UV-12 is an example of an iminosugar with activity against multiple virus families that should be investigated in further safety and efficacy studies and demonstrates potential value of this drug class as antiviral therapeutics.

  10. Antiviral activity of the Indian medicinal plant extract, Swertia chirata against herpes simplex viruses: A study by in-vitro and molecular approach

    Directory of Open Access Journals (Sweden)

    Verma H

    2008-01-01

    Full Text Available Purpose: The antiviral activity of Indian Medicinal plant extract Swertia chirata was tested against Herpes simplex virus (HSV type-1, using multiple approaches both at cellular and molecular level. Methods: Cytotoxicity, plaque reduction, virus infectivity, antigen expression and polymerase chain reaction (PCR assays were conducted to test the antiviral activity of the plant extract. Results: Swertia plant crude extract (1gm/mL at 1:64 dilution inhibited HSV-1, plaque formation at more than 70% level. HSV antigen expression and time kinetics experiments conducted by indirect immunofluorescence (IFA test, revealed a characteristic pattern of small foci of single fluorescent cells in Swertia extract treated HSV-1 infected cells at 4 hours post infection dose, suggested drug inhibited viral dissemination. Infected cell cultures treated with Swertia extract at various time intervals, tested by PCR, failed to show amplification at 12, 24-72 hours. HSV-1 infected cells treated with Acyclovir (antiviral drug did not show any amplification by PCR. Conclusions: In this preliminary study, the Indian medicinal plant extract, Swertia chirata showed antiviral properties against Herpes simplex virus type-1.

  11. Biochemical and biophysical characterization of cell-free synthesized Rift Valley fever virus nucleoprotein capsids enables in vitro screening to identify novel antivirals.

    Science.gov (United States)

    Broce, Sean; Hensley, Lisa; Sato, Tomoharu; Lehrer-Graiwer, Joshua; Essrich, Christian; Edwards, Katie J; Pajda, Jacqueline; Davis, Christopher J; Bhadresh, Rami; Hurt, Clarence R; Freeman, Beverly; Lingappa, Vishwanath R; Kelleher, Colm A; Karpuj, Marcela V

    2016-05-14

    Viral capsid assembly involves the oligomerization of the capsid nucleoprotein (NP), which is an essential step in viral replication and may represent a potential antiviral target. An in vitro transcription-translation reaction using a wheat germ (WG) extract in combination with a sandwich ELISA assay has recently been used to identify small molecules with antiviral activity against the rabies virus. Here, we examined the application of this system to viruses with capsids with a different structure, such as the Rift Valley fever virus (RVFV), the etiological agent of a severe emerging infectious disease. The biochemical and immunological characterization of the in vitro-generated RVFV NP assembly products enabled the distinction between intermediately and highly ordered capsid structures. This distinction was used to establish a screening method for the identification of potential antiviral drugs for RVFV countermeasures. These results indicated that this unique analytical system, which combines nucleoprotein oligomerization with the specific immune recognition of a highly ordered capsid structure, can be extended to various viral families and used both to study the early stages of NP assembly and to assist in the identification of potential antiviral drugs in a cost-efficient manner. Reviewed by Jeffry Skolnick and Noah Isakov. For the full reviews please go to the Reviewers' comments section.

  12. Antiviral Activity of Resveratrol against Human and Animal Viruses.

    Science.gov (United States)

    Abba, Yusuf; Hassim, Hasliza; Hamzah, Hazilawati; Noordin, Mohamed Mustapha

    2015-01-01

    Resveratrol is a potent polyphenolic compound that is being extensively studied in the amelioration of viral infections both in vitro and in vivo. Its antioxidant effect is mainly elicited through inhibition of important gene pathways like the NF-κβ pathway, while its antiviral effects are associated with inhibitions of viral replication, protein synthesis, gene expression, and nucleic acid synthesis. Although the beneficial roles of resveratrol in several viral diseases have been well documented, a few adverse effects have been reported as well. This review highlights the antiviral mechanisms of resveratrol in human and animal viral infections and how some of these effects are associated with the antioxidant properties of the compound.

  13. RNA interference-mediated intrinsic antiviral immunity in invertebrates.

    Science.gov (United States)

    Nayak, Arabinda; Tassetto, Michel; Kunitomi, Mark; Andino, Raul

    2013-01-01

    In invertebrates such as insects and nematodes, RNA interference (RNAi) provides RNA-based protection against viruses. This form of immunity restricts viral replication and dissemination from infected cells and viruses, in turn, have evolved evasion mechanisms or RNAi suppressors to counteract host defenses. Recent advances indicate that, in addition to RNAi, other related small RNA pathways contribute to antiviral functions in invertebrates. This has led to a deeper understanding of fundamental aspects of small RNA-based antiviral immunity in invertebrates and its contribution to viral spread and pathogenesis.

  14. Structure and Function of the Non-Structural Protein of Dengue Virus and its Applications in Antiviral Therapy.

    Science.gov (United States)

    Xie, Qian; Zhang, Bao; Yu, JianHai; Wu, Qinghua; Yang, Fangji; Cao, Hong; Zhao, Wei

    2017-01-01

    Dengue fever, a type of global and tropical infectious disease, and its prevention has become a challenging issue worldwide. Antibody-dependent enhancement effects and the virus pathogenic mechanism have not yet been fully elucidated, hindering the development of dengue fever prevention and suitable drug treatment. There is currently no specific prevention and therapy in clinical trials, however, in recent years, studies have focused on the pathogenesis and treatment of dengue. Research focusing on dengue virus nonstructural protein in special drugs for the prevention and control of dengue fever is a new progress leading to improved understanding regarding the prevention and control of dengue fever and suitable drugs for the treatment. The main challenges regarding the structure of dengue virus nonstructural protein and the drugs for antiviral therapy are summarized in this paper.

  15. Antiviral Activity of MK-4965, a Novel Nonnucleoside Reverse Transcriptase Inhibitor▿

    Science.gov (United States)

    Lai, Ming-Tain; Munshi, Vandna; Touch, Sinoeun; Tynebor, Robert M.; Tucker, Thomas J.; McKenna, Philip M.; Williams, Theresa M.; DiStefano, Daniel J.; Hazuda, Daria J.; Miller, Michael D.

    2009-01-01

    Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are the mainstays of therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infections. However, the effectiveness of NNRTIs can be hampered by the development of resistance mutations which confer cross-resistance to drugs in the same class. Extensive efforts have been made to identify new NNRTIs that can suppress the replication of the prevalent NNRTI-resistant viruses. MK-4965 is a novel NNRTI that possesses both diaryl ether and indazole moieties. The compound displays potency at subnanomolar concentrations against wild-type (WT), K103N, and Y181C reverse transcriptase (RT) in biochemical assays. MK-4965 is also highly potent against the WT virus and two most prevalent NNRTI-resistant viruses (viruses that harbor the K103N or the Y181C mutation), against which it had 95% effective concentrations (EC95s) of antiviral EC95 of MK-4965 was reduced approximately four- to sixfold when it was tested in 50% human serum. Moreover, MK-4965 was evaluated with a panel of 15 viruses with NNRTI resistance-associated mutations and showed a superior mutant profile to that of efavirenz but not to that of etravirine. MK-4965 was similarly effective against various HIV-1 subtypes and viruses containing nucleoside reverse transcriptase inhibitor or protease inhibitor resistance-conferring mutations. A two-drug combination study showed that the antiviral activity of MK-4965 was nonantagonistic with each of the 18 FDA-licensed drugs tested vice versa in the present study. Taken together, these in vitro data show that MK-4965 possesses the desired properties for further development as a new NNRTI for the treatment of HIV-1 infection. PMID:19289522

  16. Antiviral therapy for prevention of hepatocellular carcinoma in chronic hepatitis C

    DEFF Research Database (Denmark)

    Kimer, Nina; Dahl, Emilie Kristine; Gluud, Lise Lotte

    2012-01-01

    To determine whether antiviral therapy reduces the risk of developing hepatocellular carcinoma (HCC) in chronic hepatitis C.......To determine whether antiviral therapy reduces the risk of developing hepatocellular carcinoma (HCC) in chronic hepatitis C....

  17. Enhancement of the antiviral activity against caprine herpesvirus type 1 of Acyclovir in association with Mizoribine.

    Science.gov (United States)

    Camero, Michele; Buonavoglia, Domenico; Lucente, Maria Stella; Losurdo, Michele; Crescenzo, Giuseppe; Trerotoli, Paolo; Casalino, Elisabetta; Martella, Vito; Elia, Gabriella; Tempesta, Maria

    2017-04-01

    Caprine herpesvirus 1 (CpHV-1) infection in goats is responsible for genital lesions resembling the lesions induced by herpesvirus 2 in humans (HHV-2). The immunosuppressive drug Mizoribine (MIZ) is able to increase the antiviral activity of Acyclovir (ACV) against herpesvirus infections, raising interesting perspectives on new combined therapeutic strategies. In this study the anti-CpHV-1 activity in vitro of ACV alone or in combination with MIZ was evaluated. ACV (100μg/ml) displayed an antiviral effect on CpHV-1 replication. This inhibitory effect was higher when ACV (100μg/ml) was used in association with MIZ (20μg/ml). Other combinations of ACV and MIZ in various concentrations were not as effective as ACV 100μg/ml/MIZ 20μg/ml. These findings suggest that the association of ACV and MIZ is potentially useful for treatment of genital infection by herpesviruses. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Structural features and antiviral activity of sulphated fucans from the brown seaweed Cystoseira indica.

    Science.gov (United States)

    Mandal, Pinaki; Mateu, Cecilia Gabriela; Chattopadhyay, Kausik; Pujol, Carlos Alberto; Damonte, Elsa Beatriz; Ray, Bimalendu

    2007-01-01

    Natural compounds offer interesting pharmacological perspectives for antiviral drug development. In this study, we have analysed sulphated-fucan-containing fractions isolated from the brown seaweed Cystoseira indica. The crude water extract (CiWE) and the main fraction (CiF3) obtained by anion exchange chromatography had potent antiviral activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) without cytotoxicity for Vero cell cultures. Furthermore, they had no direct inactivating effect on virions in a virucidal assay, and lacked anticoagulant activity. The mode of action of these compounds could be mainly ascribed to an inhibitory effect on virus adsorption. Chemical, chromatographic and spectroscopic methods showed that the major polysaccharide had an apparent molecular mass of 35 kDa and contained a backbone of alpha-(1 --> 3)-linked fucopyranosyl residues substituted at C-2 with fucopyranosyl and xylopyranosyl residues. This sulphated fucan, considered the active principle of the C. indica water extract, also contained variously linked xylose and galactose units and glucuronic acid residues. Sulphate groups, if present, are located mostly at C-4 of (1 --> 3)-linked fucopyranosyl units, and appeared to be very important for the anti-herpetic activity of this polymer.

  19. The Roles of Direct Recognition by Animal Lectins in Antiviral Immunity and Viral Pathogenesis

    Directory of Open Access Journals (Sweden)

    Yang Liu

    2015-01-01

    Full Text Available Lectins are a group of proteins with carbohydrate recognition activity. Lectins are categorized into many families based on their different cellular locations as well as their specificities for a variety of carbohydrate structures due to the features of their carbohydrate recognition domain (CRD modules. Many studies have indicated that the direct recognition of particular oligosaccharides on viral components by lectins is important for interactions between hosts and viruses. Herein, we aim to globally review the roles of this recognition by animal lectins in antiviral immune responses and viral pathogenesis. The different classes of mammalian lectins can either recognize carbohydrates to activate host immunity for viral elimination or can exploit those carbohydrates as susceptibility factors to facilitate viral entry, replication or assembly. Additionally, some arthropod C-type lectins were recently identified as key susceptibility factors that directly interact with multiple viruses and then facilitate infection. Summarization of the pleiotropic roles of direct viral recognition by animal lectins will benefit our understanding of host-virus interactions and could provide insight into the role of lectins in antiviral drug and vaccine development.

  20. Antiviral Effects of ABMA against Herpes Simplex Virus Type 2 In Vitro and In Vivo.

    Science.gov (United States)

    Dai, Wenwen; Wu, Yu; Bi, Jinpeng; Wang, Shuai; Li, Fang; Kong, Wei; Barbier, Julien; Cintrat, Jean-Christophe; Gao, Feng; Gillet, Daniel; Su, Weiheng; Jiang, Chunlai

    2018-03-09

    Herpes simplex virus type 2 (HSV-2) is the causative pathogen of genital herpes and is closely associated with the occurrence of cervical cancer and human immunodeficiency virus (HIV) infection. The absence of an effective vaccine and the emergence of drug resistance to commonly used nucleoside analogs emphasize the urgent need for alternative antivirals against HSV-2. Recently, ABMA [1-adamantyl (5-bromo-2-methoxybenzyl) amine] has been demonstrated to be an inhibitor of several pathogens exploiting host-vesicle transport, which also participates in the HSV-2 lifecycle. Here, we showed that ABMA inhibited HSV-2-induced cytopathic effects and plaque formation with 50% effective concentrations of 1.66 and 1.08 μM, respectively. We also preliminarily demonstrated in a time of compound addition assay that ABMA exerted a dual antiviral mechanism by impairing virus entry, as well as the late stages of the HSV-2 lifecycle. Furthermore, in vivo studies showed that ABMA protected BALB/c mice from intravaginal HSV-2 challenge with an improved survival rate of 50% at 5 mg/kg (8.33% for the untreated virus infected control). Consequently, our study has identified ABMA as an effective inhibitor of HSV-2, both in vitro and in vivo, for the first time and presents an alternative to nucleoside analogs for HSV-2 infection treatment.