RESUMEN
BACKGROUND: Antiviral post-exposure prophylaxis with neuraminidase inhibitors can reduce the incidence of influenza and the risk of symptomatic influenza, but the efficacy of the other classes of antiviral remains unclear. To support an update of WHO influenza guidelines, this systematic review and network meta-analysis evaluated antiviral drugs for post-exposure prophylaxis of influenza. METHODS: We systematically searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Global Health, Epistemonikos, and ClinicalTrials.gov for randomised controlled trials published up to Sept 20, 2023 that evaluated the efficacy and safety of antivirals compared with another antiviral or placebo or standard care for prevention of influenza. Pairs of reviewers independently screened studies, extracted data, and assessed the risk of bias. We performed network meta-analyses with frequentist random effects model and assessed the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. The outcomes of interest were symptomatic or asymptomatic infection, admission to hospital, all-cause mortality, adverse events related to antivirals, and serious adverse events. This study is registered with PROSPERO, CRD42023466450. FINDINGS: Of 11â845 records identified by our search, 33 trials of six antivirals (zanamivir, oseltamivir, laninamivir, baloxavir, amantadine, and rimantadine) that enrolled 19â096 individuals (mean age 6·75-81·15 years) were included in this systematic review and network meta-analysis. Most of the studies were rated as having a low risk of bias. Zanamivir, oseltamivir, laninamivir, and baloxavir probably achieve important reductions in symptomatic influenza in individuals at high risk of severe disease (zanamivir: risk ratio 0·35, 95% CI 0·25-0·50; oseltamivir: 0·40, 0·26-0·62; laninamivir: 0·43, 0·30-0·63; baloxavir: 0·43, 0·23-0·79; moderate certainty) when given promptly (eg, within 48 h) after exposure to seasonal influenza. These antivirals probably do not achieve important reductions in symptomatic influenza in individuals at low risk of severe disease when given promptly after exposure to seasonal influenza (moderate certainty). Zanamivir, oseltamivir, laninamivir, and baloxavir might achieve important reductions in symptomatic zoonotic influenza in individuals exposed to novel influenza A viruses associated with severe disease in infected humans when given promptly after exposure (low certainty). Oseltamivir, laninamivir, baloxavir, and amantadine probably decrease the risk of all influenza (symptomatic and asymptomatic infection; moderate certainty). Zanamivir, oseltamivir, laninamivir, and baloxavir probably have little or no effect on prevention of asymptomatic influenza virus infection or all-cause mortality (high or moderate certainty). Oseltamivir probably has little or no effect on admission to hospital (moderate certainty). All six antivirals do not significantly increase the incidence of drug-related adverse events or serious adverse events, although the certainty of evidence varies. INTERPRETATION: Post-exposure prophylaxis with zanamivir, oseltamivir, laninamivir, or baloxavir probably decreases the risk of symptomatic seasonal influenza in individuals at high risk for severe disease after exposure to seasonal influenza viruses. Post-exposure prophylaxis with zanamivir, oseltamivir, laninamivir, or baloxavir might reduce the risk of symptomatic zoonotic influenza after exposure to novel influenza A viruses associated with severe disease in infected humans. FUNDING: World Health Organization.
Asunto(s)
Antivirales , Dibenzotiepinas , Gripe Humana , Metaanálisis en Red , Oseltamivir , Profilaxis Posexposición , Humanos , Gripe Humana/prevención & control , Antivirales/uso terapéutico , Antivirales/efectos adversos , Profilaxis Posexposición/métodos , Dibenzotiepinas/uso terapéutico , Oseltamivir/uso terapéutico , Oseltamivir/efectos adversos , Zanamivir/uso terapéutico , Zanamivir/efectos adversos , Zanamivir/administración & dosificación , Niño , Adulto , Morfolinas/uso terapéutico , Morfolinas/efectos adversos , Triazinas/uso terapéutico , Triazinas/efectos adversos , Piridonas/uso terapéutico , Piridonas/efectos adversos , Amantadina/uso terapéutico , Amantadina/efectos adversos , Piranos/uso terapéutico , Piranos/efectos adversos , Persona de Mediana Edad , Oxazinas/uso terapéutico , Oxazinas/efectos adversos , Anciano , Ensayos Clínicos Controlados Aleatorios como Asunto , Rimantadina/uso terapéutico , Rimantadina/efectos adversos , Femenino , Adolescente , Tiepinas/uso terapéutico , Tiepinas/efectos adversos , Masculino , Tiazolidinas/uso terapéutico , Tiazolidinas/efectos adversos , Adulto Joven , Guanidinas , Ácidos SiálicosRESUMEN
Baloxavir marboxil (1; BXM) is a potent drug used for treating influenza infections. The current synthetic route to BXM (1) is based on optical resolution; however, this method results in the loss of nearly 50% of the material. This study aimed to describe an efficient and simpler method for the synthesis of BXM. We achieved a stereoselective synthesis of BXM (1). The tricyclic triazinanone core possessing a chiral center was prepared via diastereoselective cyclization utilizing the readily available amino acid l-serine. The carboxyl moiety derived from l-serine was removed via photoredox decarboxylation under mild conditions to furnish the chiral tricyclic triazinanone core ((R)-14). The synthetic route demonstrated herein provides an efficient and atomically economical method for preparing this potent anti-influenza agent.
Asunto(s)
Dibenzotiepinas , Serina , Estereoisomerismo , Ciclización , Serina/química , Estructura Molecular , Dibenzotiepinas/química , Dibenzotiepinas/síntesis química , Triazinas/química , Triazinas/síntesis química , Oxidación-Reducción , Descarboxilación , Morfolinas/química , Morfolinas/síntesis química , Piridonas/química , Piridonas/síntesis química , Procesos Fotoquímicos , Antivirales/síntesis química , Antivirales/químicaRESUMEN
Baloxavir marboxil (baloxavir), approved as an anti-influenza drug in Japan in March 2018, can induce reduced therapeutic effectiveness due to PA protein substitutions. We assessed PA substitutions in clinical samples from influenza-infected children and adults pre- and post-baloxavir treatment, examining their impact on fever and symptom duration. During the 2022-2023 influenza season, the predominant circulating influenza subtype detected by cycling-probe RT-PCR was A(H3N2) (n = 234), with a minor circulation of A(H1N1)pdm09 (n = 10). Of the 234 influenza A(H3N2) viruses collected prior to baloxavir treatment, 2 (0.8%) viruses carry PA/I38T substitution. One virus was collected from a toddler and one from an adult, indicating the presence of viruses with reduced susceptibility to baloxavir, without prior exposure to the drug. Of the 54 paired influenza A(H3N2) viruses collected following baloxavir treatment, 8 (14.8%) viruses carried E23 K/G, or I38 M/T substitutions in PA. Variant calling through next-generation sequencing (NGS) showed varying proportions (6-100 %), a polymorphism and a mixture of PA/E23 K/G, and I38 M/T substitutions in the clinical samples. These eight viruses were obtained from children aged 7-14 years, with a median fever duration of 16.7 h and a median symptom duration of 93.7 h, which were similar to those of the wild type. However, the delayed viral clearance associated with the emergence of PA substitutions was observed. No substitutions conferring resistance to neuraminidase inhibitors were detected in 37 paired samples collected before and following oseltamivir treatment. These findings underscore the need for ongoing antiviral surveillance, informing public health strategies and clinical antiviral recommendations for seasonal influenza.
Asunto(s)
Sustitución de Aminoácidos , Antivirales , Dibenzotiepinas , Farmacorresistencia Viral , Subtipo H3N2 del Virus de la Influenza A , Gripe Humana , Morfolinas , Piridonas , Triazinas , Proteínas Virales , Humanos , Dibenzotiepinas/uso terapéutico , Dibenzotiepinas/farmacología , Gripe Humana/tratamiento farmacológico , Gripe Humana/virología , Subtipo H3N2 del Virus de la Influenza A/genética , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacos , Subtipo H3N2 del Virus de la Influenza A/enzimología , Triazinas/uso terapéutico , Triazinas/farmacología , Japón , Antivirales/farmacología , Antivirales/uso terapéutico , Morfolinas/uso terapéutico , Farmacorresistencia Viral/genética , Niño , Adulto , Preescolar , Adolescente , Proteínas Virales/genética , ARN Polimerasa Dependiente del ARN/genética , Femenino , Masculino , Tiepinas/uso terapéutico , Tiepinas/farmacología , Lactante , Persona de Mediana Edad , Estaciones del Año , Piridinas/uso terapéutico , Piridinas/farmacología , Adulto Joven , Subtipo H1N1 del Virus de la Influenza A/genética , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , AncianoRESUMEN
Avian influenza outbreaks, including ones caused by highly pathogenic A(H5N1) clade 2.3.4.4b viruses, have devastated animal populations and remain a threat to humans. Risk elements assessed for emerging influenza viruses include their susceptibility to approved antivirals. Here, we screened >20,000 neuraminidase (NA) or polymerase acidic (PA) protein sequences of potentially pandemic A(H5Nx), A(H7Nx), and A(H9N2) viruses that circulated globally in 2010-2023. The frequencies of NA or PA substitutions associated with reduced inhibition (RI) or highly reduced inhibition (HRI) by NA inhibitors (NAIs) (oseltamivir, zanamivir) or a cap-dependent endonuclease inhibitor (baloxavir) were low: 0.60% (137/22,713) and 0.62% (126/20,347), respectively. All tested subtypes were susceptible to NAIs and baloxavir at sub-nanomolar concentrations. A(H9N2) viruses were the most susceptible to oseltamivir, with IC50s 3- to 4-fold lower than for other subtypes (median IC50: 0.18 nM; n = 22). NA-I222M conferred RI of A(H5N1) viruses by oseltamivir (with a 26-fold IC50 increase), but NA-S246N did not reduce inhibition. PA-E23G, PA-K34R, PA-I38M/T, and the previously unreported PA-A36T caused RI by baloxavir in all subtypes tested. Avian A(H9N2) viruses endemic in Egyptian poultry predominantly acquired PA-I38V, which causes only a <3-fold decrease in the baloxavir EC50 and fails to meet the RI criteria. PA-E199A/D in A(H7Nx) and A(H9N2) viruses caused a 2- to 4-fold decrease in EC50 (close to the borderline for RI) and should be closely monitored. Our data indicate antiviral susceptibility is high among avian influenza A viruses with pandemic potential and present novel markers of resistance to existing antiviral interventions.
Asunto(s)
Antivirales , Aves , Dibenzotiepinas , Farmacorresistencia Viral , Inhibidores Enzimáticos , Genotipo , Virus de la Influenza A , Gripe Aviar , Neuraminidasa , Oseltamivir , Piridonas , Triazinas , Neuraminidasa/antagonistas & inhibidores , Neuraminidasa/genética , Antivirales/farmacología , Gripe Aviar/virología , Animales , Inhibidores Enzimáticos/farmacología , Dibenzotiepinas/farmacología , Farmacorresistencia Viral/genética , Piridonas/farmacología , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza A/genética , Virus de la Influenza A/enzimología , Triazinas/farmacología , Oseltamivir/farmacología , Aves/virología , Morfolinas/farmacología , Endonucleasas/antagonistas & inhibidores , Endonucleasas/genética , Endonucleasas/metabolismo , Subtipo H9N2 del Virus de la Influenza A/efectos de los fármacos , Subtipo H9N2 del Virus de la Influenza A/genética , Proteínas Virales/genética , Proteínas Virales/antagonistas & inhibidores , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/genética , Subtipo H5N1 del Virus de la Influenza A/enzimología , Zanamivir/farmacología , Fenotipo , Humanos , Concentración 50 InhibidoraRESUMEN
Baloxavir marboxil (BXM) is a cap-dependent nucleic acid endonuclease inhibitor, which exerts its antiviral effects after being metabolized to its active form baloxavir acid (BXA). Ethylenediamine tetra-acetic acid (EDTA) and heparin are the two most used anticoagulants in clinical blood sample collection to estimate drug levels in plasma. However, compared to heparin plasma, there is a lack of clinical pharmacokinetic data of BXA using EDTA anticoagulant tubes for blood collection. In the present study, an efficient, rapid, and sensitive ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for simultaneous quantification of BXM and its active metabolite BXA in human plasma with its isotopic baloxavir-d5 (BXA-d5) as internal standard (IS). Plasma samples (50⯵L) were undergone using acetonitrile containing 0.1â¯% formic acid a precipitant. Chromatographic separation was achieved by a Waters XBridge®C8 (2.1â¯mm × 50â¯mm, 2.5⯵m) column. The gradient mobile phase was 0.1â¯% formic acid in water (A, pH 2.8) and 0.1â¯% formic acid in acetonitrile (B) and delivered at a flow rate of 0.6â¯mL/min for 4.5â¯min. BXM and BXA were monitored using a positive electrospray triple quadrupole mass spectrometer (TRIPLE QUAD™ 6500+) via multiple reaction monitoring mode. The mass-to-charge ratios (m/z) were 572.2â247.0, 484.2â247.0 and 489.2â252.0 for BXM, BXA, and BXA-d5 (IS). Calibration curves exhibited excellent linearity in the range of 0.1-10â¯ng/mL for BXM (r2 > 0.996), and 0.3-300â¯ng/mL for BXA (r2 > 0.998). Within-run and between-run precisions in coefficients of variations were less than 11.62â¯% for BXM and less than 7.47â¯% for BXA, and accuracies in relative error were determined to be within -7.78â¯% to 5.70â¯% for BXM and -6.67â¯% to 8.56â¯% for BXA. Extraction recovery efficiency was 92.76â¯% for BXM, 95.32â¯% for BXA, and 99.26â¯% for BXA-d5, respectively. The matrix effect of BXM and BXA was in line with the requirements, where the relative deviation of the accuracy was less than 6.67â¯% and the precision was less than 6.69â¯%. The validated efficient and simple UHPLC-MS/MS method was successfully used in the pharmacokinetic study of BXM and BXA in healthy human volunteers with K2EDTA and heparin tubes for blood collection. EDTA might compete with BXA for chelating metal ions and thereby decrease the plasma ratio in whole blood, leading to approximately 50â¯% lower measurement of pharmacokinetic parameters as compared with those obtained from heparin plasma anticoagulant tubes.
Asunto(s)
Anticoagulantes , Dibenzotiepinas , Oxazinas , Piridinas , Piridonas , Espectrometría de Masas en Tándem , Humanos , Espectrometría de Masas en Tándem/métodos , Cromatografía Líquida de Alta Presión/métodos , Anticoagulantes/sangre , Anticoagulantes/farmacocinética , Dibenzotiepinas/farmacocinética , Dibenzotiepinas/sangre , Piridonas/farmacocinética , Piridonas/sangre , Piridinas/farmacocinética , Piridinas/sangre , Oxazinas/farmacocinética , Oxazinas/sangre , Morfolinas/farmacocinética , Morfolinas/sangre , Triazinas/farmacocinética , Triazinas/sangre , Reproducibilidad de los Resultados , Ácido Edético/farmacocinética , Límite de Detección , Heparina/sangre , Heparina/farmacocinéticaRESUMEN
Baloxavir acid (BXA) is a pan-influenza antiviral that targets the cap-dependent endonuclease of the polymerase acidic (PA) protein required for viral mRNA synthesis. To gain a comprehensive understanding on the molecular changes associated with reduced susceptibility to BXA and their fitness profile, we performed a deep mutational scanning at the PA endonuclease domain of an A (H1N1)pdm09 virus. The recombinant virus libraries were serially passaged in vitro under increasing concentrations of BXA followed by next-generation sequencing to monitor PA amino acid substitutions with increased detection frequencies. Enriched PA amino acid changes were each introduced into a recombinant A (H1N1)pdm09 virus to validate their effect on BXA susceptibility and viral replication fitness in vitro. The I38 T/M substitutions known to confer reduced susceptibility to BXA were invariably detected from recombinant virus libraries within 5 serial passages. In addition, we identified a novel L106R substitution that emerged in the third passage and conferred greater than 10-fold reduced susceptibility to BXA. PA-L106 is highly conserved among seasonal influenza A and B viruses. Compared to the wild-type virus, the L106R substitution resulted in reduced polymerase activity and a minor reduction of the peak viral load, suggesting the amino acid change may result in moderate fitness loss. Our results support the use of deep mutational scanning as a practical tool to elucidate genotype-phenotype relationships, including mapping amino acid substitutions with reduced susceptibility to antivirals.
Asunto(s)
Sustitución de Aminoácidos , Antivirales , Dibenzotiepinas , Farmacorresistencia Viral , Subtipo H1N1 del Virus de la Influenza A , Morfolinas , Piridonas , Triazinas , Proteínas Virales , Replicación Viral , Dibenzotiepinas/farmacología , Farmacorresistencia Viral/genética , Antivirales/farmacología , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H1N1 del Virus de la Influenza A/genética , Triazinas/farmacología , Replicación Viral/efectos de los fármacos , Piridonas/farmacología , Humanos , Morfolinas/farmacología , Proteínas Virales/genética , Animales , Tiepinas/farmacología , ARN Polimerasa Dependiente del ARN/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Perros , Células de Riñón Canino Madin Darby , Gripe Humana/virología , Gripe Humana/tratamiento farmacológico , Oxazinas/farmacologíaRESUMEN
BACKGROUND: Influenza viruses can cause zoonotic infections that pose public health risks. Surveillance of influenza A and B viruses is conducted globally; however, information on influenza C and D viruses is limited. Longitudinal monitoring of influenza C virus in humans has been conducted in several countries, but there has been no long-term monitoring of influenza D virus in humans. The public health risks associated with the influenza D virus therefore remain unknown. METHODS: We established a duplex real-time RT-PCR to detect influenza C and D viruses and analyzed respiratory specimens collected from 2144 patients in Japan with respiratory diseases between January 2018 and March 2023. We isolated viruses and conducted hemagglutination inhibition tests to examine antigenicity and focus reduction assays to determine susceptibility to the cap-dependent endonuclease inhibitor baloxavir marboxil. RESULTS: We detected three influenza C viruses belonging to the C/Kanagawa- or C/Sao Paulo-lineages, which recently circulated globally. None of the specimens was positive for the influenza D virus. The C/Yokohama/1/2022 strain, isolated from the specimen with the highest viral RNA load and belonging to the C/Kanagawa-lineage, showed similar antigenicity to the reference C/Kanagawa-lineage strain and was susceptible to baloxavir. CONCLUSIONS: Our duplex real-time RT-PCR is useful for the simultaneous detection of influenza C and D viruses from the same specimen. Adding the influenza D virus to the monitoring of the influenza C virus would help in assessing the public health risks posed by this virus.
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Dibenzotiepinas , Gammainfluenzavirus , Gripe Humana , Piridonas , Triazinas , Humanos , Japón/epidemiología , Gripe Humana/virología , Gripe Humana/epidemiología , Triazinas/farmacología , Masculino , Femenino , Gammainfluenzavirus/aislamiento & purificación , Gammainfluenzavirus/genética , Persona de Mediana Edad , Adulto , Anciano , Antivirales/uso terapéutico , Antivirales/farmacología , Morfolinas , Pruebas de Inhibición de Hemaglutinación , Preescolar , Niño , Adolescente , Adulto Joven , Thogotovirus/genética , Thogotovirus/aislamiento & purificación , Thogotovirus/clasificación , Reacción en Cadena en Tiempo Real de la Polimerasa , Lactante , Anciano de 80 o más AñosRESUMEN
High pathogenicity avian influenza is an acute zoonotic disease with high mortality in birds caused by a high pathogenicity avian influenza virus (HPAIV). Recently, HPAIV has rapidly spread worldwide and has killed many wild birds, including endangered species. Baloxavir marboxil (BXM), an anti-influenza agent used for humans, was reported to reduce mortality and virus secretion from HPAIV-infected chickens (Gallus domesticus, order Galliformes) at a dosage of ≥2.5 mg/kg when administered simultaneously with viral challenge. Application of this treatment to endangered birds requires further information on potential avian-specific toxicity caused by repeated exposure to BXM over the long term. To obtain information of potential avian-specific toxicity, a 4-wk oral repeated-dose study of BXM was conducted in chickens (n = 6 or 7 per group), which are commonly used as laboratory avian species. The study was conducted in reference to the human pharmaceutical guidelines for nonclinical repeated-dose drug toxicity studies to evaluate systemic toxicity and exposure. No adverse changes were observed in any organs examined, and dose proportional increases in systemic exposure to active pharmaceutical ingredients were noted from 12.5 to 62.5 mg/kg per day. BXM showed no toxicity to chickens at doses of up to 62.5 mg/kg per day, at which systemic exposure was approximately 71 times higher than systemic exposure at 2.5 mg/kg, the reported efficacious dosage amount, in HPAIV-infected chickens. These results also suggest that BXM could be considered safe for treating HPAIV-infected endangered birds due to its high safety margin compared with the efficacy dose. The data in this study could contribute to the preservation of endangered birds by using BXM as a means of protecting biodiversity.
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Antivirales , Pollos , Dibenzotiepinas , Morfolinas , Piridonas , Triazinas , Animales , Triazinas/administración & dosificación , Dibenzotiepinas/administración & dosificación , Administración Oral , Antivirales/administración & dosificación , Antivirales/farmacología , Morfolinas/administración & dosificación , Morfolinas/farmacología , Piridonas/administración & dosificación , Piridonas/farmacología , Piridinas/administración & dosificación , Tiepinas/administración & dosificación , Tiepinas/farmacología , Masculino , Gripe Aviar/tratamiento farmacológico , Femenino , Oxazinas , Hidroxibutiratos/administración & dosificaciónRESUMEN
We compared the duration of fever in children infected with A(H1N1)pdm09, A(H3N2), or influenza B viruses following treatment with baloxavir marboxil (baloxavir) or neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, or laninamivir). This observational study was conducted at 10 outpatient clinics across 9 prefectures in Japan during the 2012-2013 and 2019-2020 influenza seasons. Patients with influenza rapid antigen test positive were treated with one of four anti-influenza drugs. The type/subtype of influenza viruses were identified from MDCK or MDCK SIAT1 cell-grown samples using two-step real-time PCR. Daily self-reported body temperature after treatment were used to evaluate the duration of fever by treatment group and various underlying factors. Among 1742 patients <19 years old analyzed, 452 (26.0%) were A(H1N1)pdm09, 827 (48.0%) A(H3N2), and 463 (26.0%) influenza B virus infections. Among fours treatment groups, baloxavir showed a shorter median duration of fever compared to oseltamivir in univariate analysis for A(H1N1)pdm09 virus infections (baloxavir, 22.0 h versus oseltamivir, 26.7 h, P < 0.05; laninamivir, 25.5 h, and zanamivir, 25.0 h). However, this difference was not significant in multivariable analyses. For A(H3N2) virus infections, there were no statistically significant differences observed (20.3, 21.0, 22.0, and 19.0 h) uni- and multivariable analyses. For influenza B, baloxavir shortened the fever duration by approximately 15 h than NAIs (20.3, 35.0, 34.3, and 34.1 h), as supported by uni- and multivariable analyses. Baloxavir seems to have comparable clinical effectiveness with NAIs on influenza A but can be more effective for treating pediatric influenza B virus infections than NAIs.
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Antivirales , Dibenzotiepinas , Fiebre , Guanidinas , Subtipo H1N1 del Virus de la Influenza A , Subtipo H3N2 del Virus de la Influenza A , Virus de la Influenza B , Gripe Humana , Morfolinas , Oseltamivir , Piranos , Piridonas , Ácidos Siálicos , Triazinas , Zanamivir , Humanos , Gripe Humana/tratamiento farmacológico , Gripe Humana/virología , Antivirales/uso terapéutico , Antivirales/farmacología , Virus de la Influenza B/efectos de los fármacos , Virus de la Influenza B/genética , Niño , Zanamivir/uso terapéutico , Zanamivir/análogos & derivados , Zanamivir/farmacología , Triazinas/uso terapéutico , Triazinas/farmacología , Guanidinas/uso terapéutico , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacos , Subtipo H3N2 del Virus de la Influenza A/genética , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Piridonas/uso terapéutico , Dibenzotiepinas/uso terapéutico , Japón , Femenino , Masculino , Preescolar , Oseltamivir/uso terapéutico , Fiebre/tratamiento farmacológico , Fiebre/virología , Adolescente , Morfolinas/uso terapéutico , Lactante , Estaciones del Año , Tiepinas/uso terapéutico , Tiepinas/farmacología , Oxazinas/uso terapéutico , Factores de Tiempo , Benzoxazinas/uso terapéuticoRESUMEN
BACKGROUND: The transmission of influenza virus in households, especially by children, is a major route of infection. Prior studies suggest that timely antiviral treatment of ill cases may reduce infection in household contacts. The aim of the study was to compare the effects of oseltamivir (OTV) and baloxavir marboxil (BXM) treatment of index cases on the secondary attack rate (SAR) of influenza within household. METHODS: A post hoc analysis was done in BLOCKSTONE trial-a placebo-controlled, double-blinded post-exposure prophylaxis of BXM. Data were derived from the laboratory-confirmed index cases' household contacts who received placebo in the trial and also from household members who did not participate in the trial but completed illness questionnaires. To assess the SAR of household members, multivariate analyses adjusted for factors including age, vaccination status, and household size were performed and compared between contacts of index cases treated with BXM or OTV. RESULTS: In total, 185 index cases (116 treated with BXM and 69 treated with OTV) and 410 household contacts (201 from trial, 209 by questionnaire) were included. The Poisson regression modeling showed that the SAR in household contacts of index cases treated with BXM and OTV was 10.8% and 18.5%, respectively; the adjusted relative reduction in SAR was 41.8% (95% confidence interval: 1.0%-65.7%, p = 0.0456) greater with BXM than OTV. Similar reductions were found in contacts from the trial and those included by questionnaire. CONCLUSION: BXM treatment of index cases appeared to result in a greater reduction in secondary household transmission than OTV treatment.
Asunto(s)
Antivirales , Dibenzotiepinas , Composición Familiar , Gripe Humana , Morfolinas , Oseltamivir , Profilaxis Posexposición , Piridonas , Triazinas , Humanos , Gripe Humana/tratamiento farmacológico , Gripe Humana/prevención & control , Gripe Humana/transmisión , Piridonas/uso terapéutico , Antivirales/uso terapéutico , Triazinas/uso terapéutico , Dibenzotiepinas/uso terapéutico , Femenino , Masculino , Oseltamivir/uso terapéutico , Adulto , Adolescente , Niño , Persona de Mediana Edad , Adulto Joven , Profilaxis Posexposición/métodos , Preescolar , Morfolinas/uso terapéutico , Tiepinas/uso terapéutico , Método Doble Ciego , Lactante , Piridinas/uso terapéutico , Anciano , Oxazinas/uso terapéuticoRESUMEN
BACKGROUND AND OBJECTIVES: Amidst limited influenza treatment options, evaluating the safety of Oseltamivir and Baloxavir Marboxil is crucial, particularly given their comparable efficacy. This study investigates post-market safety profiles, exploring adverse events (AEs) and their drug associations to provide essential clinical references. METHODS: A meticulous analysis of FDA Adverse Event Reporting System (FAERS) data spanning the first quarter of 2004 to the fourth quarter of 2022 was conducted. Using data mining techniques like reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Propagation Neural Network, and Multiple Gamma Poisson Shrinkage, AEs related to Oseltamivir and Baloxavir Marboxil were examined. Venn analysis compared and selected specific AEs associated with each drug. RESULTS: Incorporating 15,104 Oseltamivir cases and 1,594 Baloxavir Marboxil cases, Wain analysis unveiled 21 common AEs across neurological, psychiatric, gastrointestinal, dermatological, respiratory, and infectious domains. Oseltamivir exhibited 221 significantly specific AEs, including appendicolith [ROR (95% CI), 459.53 (340.88 â¼ 619.47)], acne infantile [ROR (95% CI, 368.65 (118.89 â¼ 1143.09)], acute macular neuroretinopathy [ROR (95% CI), 294.92 (97.88 â¼ 888.64)], proctitis [ROR (95% CI), 245.74 (101.47 â¼ 595.31)], and Purpura senile [ROR (95% CI), 154.02 (81.96 â¼ 289.43)]. designated adverse events (DMEs) associated with Oseltamivir included fulminant hepatitis [ROR (95% CI), 12.12 (8.30-17.72), n=27], ventricular fibrillation [ROR (95% CI), 7.68 (6.01-9.83), n=64], toxic epidermal necrolysis [ROR (95% CI), 7.21 (5.74-9.05), n=75]. Baloxavir Marboxil exhibited 34 specific AEs, including Melaena [ROR (95% CI), 21.34 (14.15-32.18), n = 23], cystitis haemorrhagic [ROR (95% CI), 20.22 (7.57-54.00), n = 4], ileus paralytic [ROR (95% CI), 18.57 (5.98-57.71), n = 3], and haemorrhagic diathesis [ROR (95% CI), 16.86 (5.43-52.40)), n = 3]. DMEs associated with Baloxavir Marboxil included rhabdomyolysis [ROR (95% CI), 15.50 (10.53 â¼ 22.80), n = 26]. CONCLUSION: Monitoring fulminant hepatitis during Oseltamivir treatment, especially in patients with liver-related diseases, is crucial. Oseltamivir's potential to induce abnormal behavior, especially in adolescents, necessitates special attention. Baloxavir Marboxil, with lower hepatic toxicity, emerges as a potential alternative for patients with liver diseases. During Baloxavir Marboxil treatment, focused attention on the occurrence of rhabdomyolysis is advised, necessitating timely monitoring of relevant indicators for those with clinical manifestations. The comprehensive data aims to provide valuable insights for clinicians and healthcare practitioners, facilitating an understanding of the safety profiles of these influenza treatments in real-world scenarios.
Asunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos , Antivirales , Dibenzotiepinas , Morfolinas , Oseltamivir , Farmacovigilancia , Triazinas , United States Food and Drug Administration , Humanos , Dibenzotiepinas/efectos adversos , Triazinas/efectos adversos , Estados Unidos , Oseltamivir/efectos adversos , Antivirales/efectos adversos , Femenino , Masculino , Morfolinas/efectos adversos , Adulto , Persona de Mediana Edad , Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Adolescente , Piridonas/efectos adversos , Adulto Joven , Anciano , Gripe Humana/tratamiento farmacológico , Niño , Triazoles/efectos adversos , Tiepinas/efectos adversos , Pirazinas/efectos adversos , Piridinas/efectos adversos , Preescolar , Oxazinas/efectos adversosRESUMEN
BACKGROUND: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has lasted for three years. Coinfection with seasonal influenza may occur resulting in more severe diseases. The interaction between these two viruses for infection and the effect of antiviral treatment remains unclear. METHODS: A SARS-CoV-2 and influenza H1N1 coinfection model on Calu-3 cell line was established, upon which the simultaneous and sequential coinfection was evaluated by comparing the viral load. The efficacy of molnupiravir and baloxavir against individual virus and coinfection were also studied. RESULTS: The replication of SARS-CoV-2 was significantly interfered when the influenza virus was infected simultaneously or in advance (p < 0.05). On the contrary, the replication of the influenza virus was not affected by the SARS-CoV-2. Molnupiravir monotherapy had significant inhibitory effect on SARS-CoV-2 when the concentration reached to 6.25 µM but did not show any significant anti-influenza activity. Baloxavir was effective against influenza within the dosage range and showed significant effect of anti-SARS-CoV-2 at 16 µM. In the treatment of coinfection, molnupiravir had significant effect for SARS-CoV-2 from 6.25 µM to 100 µM and inhibited H1N1 at 100 µM (p < 0.05). The tested dosage range of baloxavir can inhibit H1N1 significantly (p < 0.05), while at the highest concentration of baloxavir did not further inhibit SARS-CoV-2, and the replication of SARS-CoV-2 significantly increased in lower concentrations. Combination treatment can effectively inhibit influenza H1N1 and SARS-CoV-2 replication during coinfection. Compared with molnupiravir or baloxavir monotherapy, combination therapy was more effective in less dosage to inhibit the replication of both viruses. CONCLUSIONS: In coinfection, the replication of SARS-CoV-2 would be interfered by influenza H1N1. Compared with molnupiravir or baloxavir monotherapy, treatment with a combination of molnupiravir and baloxavir should be considered for early treatment in patients with SARS-CoV-2 and influenza coinfection.
Asunto(s)
Antivirales , COVID-19 , Coinfección , Dibenzotiepinas , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana , SARS-CoV-2 , Carga Viral , Replicación Viral , Antivirales/farmacología , Antivirales/uso terapéutico , Humanos , SARS-CoV-2/efectos de los fármacos , Gripe Humana/tratamiento farmacológico , Gripe Humana/virología , Coinfección/tratamiento farmacológico , Coinfección/virología , Replicación Viral/efectos de los fármacos , Dibenzotiepinas/uso terapéutico , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , COVID-19/virología , Carga Viral/efectos de los fármacos , Piridonas/farmacología , Piridonas/uso terapéutico , Línea Celular , Morfolinas/farmacología , Morfolinas/uso terapéutico , Triazinas/farmacología , Triazinas/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Hidroxilaminas/farmacología , Hidroxilaminas/uso terapéutico , Tiazoles/farmacología , Tiazoles/uso terapéutico , Citidina/análogos & derivadosRESUMEN
The large Bunyavirales order includes several families of viruses with a segmented ambisense (-) RNA genome and a cytoplasmic life cycle that starts by synthesizing viral mRNA. The initiation of transcription, which is common to all members, relies on an endonuclease activity that is responsible for cap-snatching. In La Crosse virus, an orthobunyavirus, it has previously been shown that the cap-snatching endonuclease resides in the N-terminal domain of the L protein. Orthobunyaviruses are transmitted by arthropods and cause diseases in cattle. However, California encephalitis virus, La Crosse virus and Jamestown Canyon virus are North American species that can cause encephalitis in humans. No vaccines or antiviral drugs are available. In this study, three known Influenza virus endonuclease inhibitors (DPBA, L-742,001 and baloxavir) were repurposed on the La Crosse virus endonuclease. Their inhibition was evaluated by fluorescence resonance energy transfer and their mode of binding was then assessed by differential scanning fluorimetry and microscale thermophoresis. Finally, two crystallographic structures were obtained in complex with L-742,001 and baloxavir, providing access to the structural determinants of inhibition and offering key information for the further development of Bunyavirales endonuclease inhibitors.
Asunto(s)
Antivirales , Endonucleasas , Virus La Crosse , Triazinas , Virus La Crosse/efectos de los fármacos , Virus La Crosse/enzimología , Antivirales/farmacología , Antivirales/química , Endonucleasas/antagonistas & inhibidores , Endonucleasas/metabolismo , Endonucleasas/química , Dibenzotiepinas , Morfolinas/farmacología , Morfolinas/química , Piridonas/farmacología , Piridonas/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Transferencia Resonante de Energía de Fluorescencia , Humanos , Animales , Proteínas Virales/antagonistas & inhibidores , Proteínas Virales/química , Proteínas Virales/metabolismoRESUMEN
Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic bunyavirus with a fatality rate of up to 40%. Currently, there are no licensed antiviral drugs for the treatment of CCHF; thus, the World Health Organization (WHO) listed the disease as a priority. A unique viral transcription initiation mechanism called "cap-snatching" is shared by influenza viruses and bunyaviruses. Thus, we tested whether baloxavir (an FDA-approved anti-influenza drug that targets the "cap-snatching" mechanism) could inhibit CCHFV infection. In cell culture, baloxavir acid effectively inhibited CCHFV infection and targeted CCHFV RNA transcription/replication. However, it has weak oral bioavailability. Baloxavir marboxil (the oral prodrug of baloxavir) failed to protect mice against a lethal dose challenge of CCHFV. To solve this problem, baloxavir sodium was synthesized owing to its enhanced aqueous solubility and pharmacokinetic properties. It consistently and significantly improved survival rates and decreased tissue viral loads. This study identified baloxavir sodium as a novel scaffold structure and mechanism of anti-CCHF compound, providing a promising new strategy for clinical treatment of CCHF after further optimization.
Asunto(s)
Antivirales , Dibenzotiepinas , Morfolinas , Piridinas , Piridonas , Triazinas , Replicación Viral , Animales , Morfolinas/farmacología , Morfolinas/farmacocinética , Morfolinas/química , Antivirales/farmacología , Antivirales/farmacocinética , Antivirales/química , Dibenzotiepinas/farmacología , Dibenzotiepinas/farmacocinética , Ratones , Piridinas/farmacología , Piridinas/farmacocinética , Piridinas/química , Replicación Viral/efectos de los fármacos , Triazinas/farmacología , Triazinas/farmacocinética , Triazinas/química , Triazinas/uso terapéutico , Piridonas/farmacología , Piridonas/farmacocinética , Piridonas/química , Tiepinas/farmacología , Tiepinas/uso terapéutico , Tiepinas/farmacocinética , Tiepinas/química , Carga Viral/efectos de los fármacos , Chlorocebus aethiops , Células Vero , Femenino , Oxazinas/farmacología , Oxazinas/farmacocinética , Oxazinas/uso terapéutico , Ratones Endogámicos BALB C , Humanos , Tiazoles/farmacología , Tiazoles/farmacocinética , Tiazoles/químicaRESUMEN
STUDY OBJECTIVE: To determine whether there is a signal for gastrointestinal (GI) or intracranial (IC) hemorrhage associated with the use of antiviral medications for influenza in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. DESIGN: Disproportionality analysis. DATA SOURCE: The FAERS database was searched using OpenVigil 2.1 to identify GI and IC hemorrhage events reported between 2004 and 2022. MEASUREMENTS: Antiviral medications for influenza included the following: oseltamivir, zanamivir, peramivir, and baloxavir marboxil. Hemorrhage events were identified using Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries for GI and IC hemorrhages. Reporting odds ratios (RORs) were calculated to compare the occurrence of GI and IC hemorrhage events between antiviral drugs for influenza and (i) all other medications and (ii) antibiotics. RORs were also calculated for each of the individual antiviral medications. MAIN RESULTS: A total of 245 cases of GI hemorrhage and 23 cases of IC hemorrhage were identified in association with four antivirals. In comparison with all other drugs, the RORs of GI hemorrhage for oseltamivir, zanamivir, peramivir, baloxavir, and all antivirals combined were 1.17, 0.62, 4.44, 2.53, and 1.22, respectively, indicating potential variations in GI hemorrhage risk among the antivirals. In contrast, in comparison with all other drugs, the RORs of IC hemorrhage for oseltamivir (0.44), zanamivir (0.16), baloxavir (0.44), and all antivirals combined (0.41) were less than 1.0 which is consistent with no elevated risk of IC hemorrhage. CONCLUSION: In this study, some signals for GI hemorrhage were observed, particularly for peramivir and baloxavir marboxil. Further investigation is warranted to better understand and evaluate the potential risks of GI hemorrhage associated with antiviral treatments for influenza.
Asunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos , Antivirales , Bases de Datos Factuales , Dibenzotiepinas , Hemorragia Gastrointestinal , Gripe Humana , Oseltamivir , United States Food and Drug Administration , Humanos , Antivirales/efectos adversos , Estados Unidos/epidemiología , Gripe Humana/tratamiento farmacológico , Gripe Humana/epidemiología , Hemorragia Gastrointestinal/inducido químicamente , Hemorragia Gastrointestinal/epidemiología , Oseltamivir/efectos adversos , Dibenzotiepinas/efectos adversos , Ácidos Carbocíclicos , Hemorragias Intracraneales/inducido químicamente , Hemorragias Intracraneales/epidemiología , Zanamivir/efectos adversos , Zanamivir/uso terapéutico , Triazinas/efectos adversos , Persona de Mediana Edad , Masculino , Guanidinas/efectos adversos , Morfolinas/efectos adversos , Piridonas/efectos adversos , Femenino , Adulto , AncianoRESUMEN
Antiviral susceptibility of influenza viruses was assessed using a high-content imaging-based neutralization test. Cap-dependent endonuclease inhibitors, baloxavir and AV5116, were superior to AV5115 against type A viruses, and AV5116 was most effective against PA mutants tested. However, these three inhibitors displayed comparable activity (EC50 8-22 nM) against type C viruses from six lineages. Banana lectin and a monoclonal antibody, YA3, targeting the hemagglutinin-esterase protein effectively neutralized some, but not all, type C viruses.
Asunto(s)
Antivirales , Dibenzotiepinas , Triazinas , Antivirales/farmacología , Humanos , Triazinas/farmacología , Dibenzotiepinas/farmacología , Gammainfluenzavirus/efectos de los fármacos , Gammainfluenzavirus/genética , Morfolinas/farmacología , Piridonas/farmacología , Animales , Anticuerpos Monoclonales/farmacología , Células de Riñón Canino Madin Darby , Perros , Ciclopropanos/farmacología , Virus de la Influenza A/efectos de los fármacos , Pruebas de Neutralización , Piridinas/farmacologíaRESUMEN
BACKGROUND: Influenza virus is a kind of RNA virus. Nowadays, the high incidence of influenza and the morbidity and mortality of epidemic influenza are substantial. It has been reported that one hundred million people in the world are infected with influenza viruses, and two hundred and fifty thousand to five hundred thousand people die from the flu per year. In 2021, the number of infected persons in China was reported to be 654,700, and 0.07% of the infected persons died. The flu has caused a serious threat to human survival. Although several drugs, such as Zanamivir, Oseltamivir, Peramivir, and Laninamivir, have been used in clinics for the treatment of the influenza virus, there are some shortcomings of these drugs. The strain of influenza H5N1 (avian influenza) has been found to resist the effective drug Oseltamivir. Thus, there is an urgent demand to discover new influenza virus inhibitors to overcome the emergence of influenza antigens. AIMS: This study aimed to develop new influenza virus inhibitors based on the rupestonic acid parent core. OBJECTIVE: The rupestonic acid L-ephedrine ester (A) and rupestonic acid L-ephedrine complex (B) were synthesized in this work for the development of influenza virus inhibitors. METHODS: The target compounds were synthesized using rupestonic acid and L-ephedrine as starting materials. Their structures were characterized by 1H NMR and 13C NMR, and the purity was determined by HPLC. Then, their preliminary in vitro influenza activity was evaluated using Oseltamivir as a reference drug. RESULTS: The results showed that the synthesized rupestonic acid L-ephedrine derivatives A and B were more potent influenza virus inhibitors against the strains of A/PR/8/34 (H1N1) and A/FM/1/47 (H1N1) with the IC50 values of 51.0, 51.0 µM and 441.0, 441.0 µM, respectively, than that of rupestonic acid. By comparing the IC50 of compounds A and B, compound A can be regarded as a very promising lead compound for the development of influenza virus inhibitors. CONCLUSION: The rupestonic acid L-ephedrine ester (A) and rupestonic acid L-ephedrine complex (B) were synthesized and characterized using 1H NMR and 13C NMR. Moreover, their purity was determined by HPLC. Both compounds A and B exhibited more potent activities against the strains of A/PR/8/34 (H1N1) and A/FM/1/47 (H1N1) than rupestonic acid. Compound A can be regarded as a very promising lead compound for the development of influenza virus inhibitors. Based on these results, more rupestonic acid derivatives will be designed and synthesized in the future for the development of influenza virus inhibitors.
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Antivirales , Antivirales/farmacología , Antivirales/síntesis química , Antivirales/química , Humanos , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Células de Riñón Canino Madin Darby , Animales , Estructura Molecular , Relación Dosis-Respuesta a Droga , Piranos/farmacología , Piranos/síntesis química , Piranos/química , Perros , Gripe Humana/tratamiento farmacológico , Gripe Humana/virología , Dibenzotiepinas/farmacología , Dibenzotiepinas/síntesis química , Sesquiterpenos , AzulenosRESUMEN
Influenza viruses (IVs) threaten global human health due to the high morbidity, infection, and mortality rates. Currently, the influenza drugs recommended by the Food and Drug Administration are oseltamivir, zanamivir, peramivir, and baloxavir marboxil. These recommended antivirals are currently effective for major subtypes of IVs as the compounds target conserved domains in neuraminidase or polymerase acidic (PA) protein. However, this trend may gradually change due to the selection of antiviral drugs and the natural evolution of IVs. Therefore, there is an urgent need to develop drugs related to the treatment of influenza to deal with the next pandemic. Here, we summarized the cutting-edge research in mechanism of action, inhibitory activity, and clinical efficacy of drugs that have been approved and drugs that are still in clinical trials for influenza treatment. We hope this review will provide up-to-date and comprehensive information on influenza antivirals and generate hypotheses for screens and development of new broad-spectrum influenza drugs in the near future.
Asunto(s)
Antivirales , Ensayos Clínicos como Asunto , Desarrollo de Medicamentos , Gripe Humana , Humanos , Antivirales/farmacología , Antivirales/uso terapéutico , Dibenzotiepinas , Gripe Humana/tratamiento farmacológico , Gripe Humana/virología , Morfolinas , Orthomyxoviridae/efectos de los fármacos , Piridonas , Triazinas , Zanamivir/farmacología , Zanamivir/uso terapéuticoRESUMEN
While clinical trials have illuminated both the virological and clinical efficacy of baloxavir for influenza and post-treatment viral resistance, these aspects warrant further study in real-world settings. In response, we executed a prospective, observational study of the Japanese 2022-2023 influenza season. A cohort of 73 A(H3N2)-diagnosed outpatients-36 treated with baloxavir, 20 with oseltamivir, and 17 with other neuraminidase inhibitors (NAIs)-were analyzed. Viral samples were collected before and after administering an antiviral on days 1, 5, and 10, respectively. Cultured viruses were amplified using RT-PCR and sequenced to detect mutations. Fever and other symptoms were tracked via self-reporting diaries. In the baloxavir cohort, viral detection was 11.1% (4/36) and 0% (0/36) on day 5 and day 10, respectively. Two isolates from day 5 (5.6%, 2/36) manifested I38T/M-substitutions in the polymerase acidic protein (PA). For oseltamivir and other NAIs, viral detection rates were 60.0% (12/20) and 52.9% (9/17) on day 5, and 16.7% (3/18) and 6.3% (1/16) on day 10, respectively. No oseltamivir-resistant neuraminidase mutations were identified after treatment. Median fever durations for the baloxavir, oseltamivir, and other NAI cohorts were 27.0, 38.0, and 36.0 h, respectively, with no significant difference. Two patients harboring PA I38T/M-substitutions did not exhibit prolonged fever or other symptoms. These findings affirm baloxavir's virological and clinical effectiveness against A(H3N2) in the 2022-2023 season and suggest limited clinical influence of post-treatment resistance emergence.
Asunto(s)
Dibenzotiepinas , Gripe Humana , Morfolinas , Triazinas , Humanos , Gripe Humana/tratamiento farmacológico , Oseltamivir/uso terapéutico , Oseltamivir/farmacología , Neuraminidasa/genética , Neuraminidasa/uso terapéutico , Subtipo H3N2 del Virus de la Influenza A/genética , Pacientes Ambulatorios , Estaciones del Año , Estudios Prospectivos , Antivirales/uso terapéutico , Antivirales/farmacología , Piridonas/uso terapéutico , Inhibidores Enzimáticos/farmacología , Guanidinas/farmacología , Fiebre/tratamiento farmacológicoRESUMEN
Seasonal or pandemic illness caused by influenza A viruses (IAVs) is a major public health concern due to the high morbidity and notable mortality. Although there are several approved drugs targeting different mechanisms, the emergence of drug resistance calls for new drug candidates that can be used alone or in combinations. Small-molecule IAV entry inhibitor, ING-1466, binds to hemagglutinin (HA) and blocks HA-mediated viral infection. Here, we show that this inhibitor demonstrates preventive and therapeutic effects in a mouse model of IAV with substantial improvement in the survival rate. When administered orally it elicits a therapeutic effect in mice, even after the well-established infection. Moreover, the combination of ING-1466 with oseltamivir phosphate or baloxavir marboxil enhances the therapeutic effect in a synergistic manner. Overall, ING-1466 has excellent oral bioavailability and in vitro absorption, distribution, metabolism, excretion, and toxicity profile, suggesting that it can be developed for monotherapy or combination therapy for the treatment of IAV infections.