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International Journal of Molecular... May 2024Lefamulin is a first-in-class systemic pleuromutilin antimicrobial and potent inhibitor of bacterial translation, and the most recent novel antimicrobial approved for...
Lefamulin is a first-in-class systemic pleuromutilin antimicrobial and potent inhibitor of bacterial translation, and the most recent novel antimicrobial approved for the treatment of community-acquired pneumonia (CAP). It exhibits potent antibacterial activity against the most prevalent bacterial pathogens that cause typical and atypical pneumonia and other infectious diseases. Early studies indicate additional anti-inflammatory activity. In this study, we further investigated the immune-modulatory activity of lefamulin in the influenza A/H1N1 acute respiratory distress syndrome (ARDS) model in BALB/c mice. Comparators included azithromycin, an anti-inflammatory antimicrobial, and the antiviral oseltamivir. Lefamulin significantly decreased the total immune cell infiltration, specifically the neutrophils, inflammatory monocytes, CD4 and CD8 T-cells, NK cells, and B-cells into the lung by Day 6 at both doses tested compared to the untreated vehicle control group (placebo), whereas azithromycin and oseltamivir did not significantly affect the total immune cell counts at the tested dosing regimens. Bronchioalveolar lavage fluid concentrations of pro-inflammatory cytokines and chemokines including TNF-α, IL-6, IL-12p70, IL-17A, IFN-γ, and GM-CSF were significantly reduced, and MCP-1 concentrations were lowered (not significantly) by lefamulin at the clinically relevant 'low' dose on Day 3 when the viral load peaked. Similar effects were also observed for oseltamivir and azithromycin. Lefamulin also decreased the viral load (TCID) by half a log10 by Day 6 and showed positive effects on the gross lung pathology and survival. Oseltamivir and lefamulin were efficacious in the suppression of the development of influenza-induced bronchi-interstitial pneumonia, whereas azithromycin did not show reduced pathology at the tested treatment regimen. The observed anti-inflammatory and immune-modulatory activity of lefamulin at the tested treatment regimens highlights a promising secondary pharmacological property of lefamulin. While these results require confirmation in a clinical trial, they indicate that lefamulin may provide an immune-modulatory activity beyond its proven potent antibacterial activity. This additional activity may benefit CAP patients and potentially prevent acute lung injury (ALI) and ARDS.
Topics: Animals; Influenza A Virus, H1N1 Subtype; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections; Disease Models, Animal; Diterpenes; Cytokines; Azithromycin; Oseltamivir; Female; Lung; Antiviral Agents; Tetrahydronaphthalenes; Respiratory Distress Syndrome; Immunomodulating Agents; Bronchoalveolar Lavage Fluid; Polycyclic Compounds; Thioglycolates
PubMed: 38791439
DOI: 10.3390/ijms25105401 -
Journal of Veterinary Science Jan 2024Canine parvoviral enteritis (CPE) is a fatal disease worldwide. The treatment of CPE is based mainly on supportive and symptomatic treatment. Antiviral addition to the...
BACKGROUND
Canine parvoviral enteritis (CPE) is a fatal disease worldwide. The treatment of CPE is based mainly on supportive and symptomatic treatment. Antiviral addition to the treatment may result in a higher survival.
OBJECTIVES
This study evaluated the effects of antiviral treatments with a standardized treatment (ST) on the clinical and inflammatory response of dogs with naturally occurring CPE.
METHODS
Twenty-eight dogs with CPE caused by canine parvovirus type 2 were divided randomly into treatment groups. The ST group received fluid, antibiotic, antiemetic, and deworming treatments. The antiviral treatment groups received the same ST with an additional antiviral drug, recombinant feline interferon omega (rFeIFN-ω), oseltamivir (OSEL) or famciclovir (FAM).
RESULTS
Compared to the healthy control, the tumor necrosis factor-α, interleukin-1β, interferon (IFN)-α, IFN-γ, haptoglobin, and C-reactive protein values were high ( < 0.05) on day zero. At presentation, mild lymphopenia, neutropenia, and a high neutrophil to lymphocyte (LYM) ratio (NLR) were also observed. Adding rFeIFN-ω to the ST produced the best improvement in the clinical score with a decreased NLR, while leucocytes remained low and inflammatory markers stayed high on day three. The survival rates of the groups were 85.7% in ST+IFN, 71.4% in ST+OSEL, 71.4% in ST+FAM, and 57.1% in ST groups on day seven.
CONCLUSIONS
Antiviral drugs may be valuable in treating CPE to improve the clinical signs and survival. In addition, the decrease in NLR in favor of LYM may be an indicator of the early prognosis before the improvement of leukocytes, cytokines, and acute phase proteins in CPE.
Topics: Animals; Dogs; Cats; Parvoviridae Infections; Parvovirus, Canine; Oseltamivir; Antiviral Agents; Enteritis; Dog Diseases; Cat Diseases
PubMed: 38311324
DOI: 10.4142/jvs.23139 -
Antiviral Research Sep 2023Clade 2.3.4.4b highly pathogenic avian influenza (HPAI) A(H5N1) viruses that are responsible for devastating outbreaks in birds and mammals pose a potential threat to...
Clade 2.3.4.4b highly pathogenic avian influenza (HPAI) A(H5N1) viruses that are responsible for devastating outbreaks in birds and mammals pose a potential threat to public health. Here, we evaluated their susceptibility to influenza antivirals. Of 1,015 sequences of HPAI A(H5N1) viruses collected in the United States during 2022, eight viruses (∼0.8%) had a molecular marker of drug resistance to an FDA-approved antiviral: three adamantane-resistant (M2-V27A), four oseltamivir-resistant (NA-H275Y), and one baloxavir-resistant (PA-I38T). Additionally, 31 viruses contained mutations that may reduce susceptibility to inhibitors of neuraminidase (NA) (n = 20) or cap-dependent endonuclease (CEN) (n = 11). A panel of 22 representative viruses was tested phenotypically. Overall, clade 2.3.4.4b A(H5N1) viruses lacking recognized resistance mutations were susceptible to FDA-approved antivirals. Oseltamivir was least potent at inhibiting NA activity, while the investigational NA inhibitor AV5080 was most potent, including against NA mutants. A novel NA substitution T438N conferred 12-fold reduced inhibition by zanamivir, and in combination with the known marker N295S, synergistically affected susceptibility to all five NA inhibitors. In cell culture-based assays HINT and IRINA, the PA-I38T virus displayed 75- to 108-fold and 37- to 78-fold reduced susceptibility to CEN inhibitors, baloxavir and the investigational AV5116, respectively. Viruses with PA-I38M or PA-A37T showed 5- to 10-fold reduced susceptibilities. As HPAI A(H5N1) viruses continue to circulate and evolve, close monitoring of drug susceptibility is needed for risk assessment and to inform decisions regarding antiviral stockpiling.
Topics: Animals; United States; Antiviral Agents; Oseltamivir; Influenza A Virus, H5N1 Subtype; Influenza in Birds; Enzyme Inhibitors; Birds; Mammals; Drug Resistance, Viral; Neuraminidase
PubMed: 37494978
DOI: 10.1016/j.antiviral.2023.105679 -
Case Reports in Pediatrics 2023Oseltamivir is a neuraminidase inhibitor used to treat acute influenza A or B in adult and pediatric patients. Adverse reactions are usually mild. Here, we report novel...
Oseltamivir is a neuraminidase inhibitor used to treat acute influenza A or B in adult and pediatric patients. Adverse reactions are usually mild. Here, we report novel side effects associated with oseltamivir. The patient was an 11-year-old girl who developed lower lip cheilitis and stomatitis, after taking oseltamivir. Her symptoms and signs resolved within 36 h of oseltamivir discontinuation. She has clinically fully recovered and has remained well.
PubMed: 38094904
DOI: 10.1155/2023/8618245 -
Neurology India Jan 2024Infection is an important trigger of myasthenic crisis (MC), and those infections manifest with pneumonia and muscle involvement may result in more frequent MC. We...
Infection is an important trigger of myasthenic crisis (MC), and those infections manifest with pneumonia and muscle involvement may result in more frequent MC. We report two myasthenia gravis (MG) patients with H1N1 infection, and highlight the reasons for deterioration. Two patients with MG had H1N1 infection. The diagnosis of MG was confirmed by neostigmine, repetitive nerve stimulation, and anti-acetylcholine receptor antibody tests. H1N1 was confirmed by nucleic acid detection study, and myositis by creatinine kinase. The patient with pneumonia and myositis had MC needing mechanical ventilation for 10 days, and the other patient without myositis did not have MC. They were treated with oseltamivir 75 mg twice daily for 5 days, and the patients with MC received ceftriaxone intravenously. Both the patients were on prednisolone and azathioprine, and none received prior H1N1 vaccination. The lady with MC with myositis was discharged on day 27 in wheelchair bound state, and the other one patient without myositis or MC was discharged on 6th day with full recovery. These patients highlight the need for evaluation for myositis along with pneumonia in the MG patients with H1N1 infection. Vaccination in MG patients on immunosuppression may be useful.
Topics: Humans; Influenza A Virus, H1N1 Subtype; Myasthenia Gravis; Myositis; Neostigmine; Pneumonia
PubMed: 38443018
DOI: 10.4103/neuroindia.NI_482_19 -
ACS Omega Nov 2023Drug failure during experimental procedures due to low bioactivity presents a significant challenge. To mitigate this risk and enhance compound bioactivities, predicting...
Drug failure during experimental procedures due to low bioactivity presents a significant challenge. To mitigate this risk and enhance compound bioactivities, predicting bioactivity classes during lead optimization is essential. The existing studies on structure-activity relationships have highlighted the connection between the chemical structures of compounds and their bioactivity. However, these studies often overlook the intricate relationship between drugs and bioactivity, which encompasses multiple factors beyond the chemical structure alone. To address this issue, we propose the BioAct-Het model, employing a heterogeneous siamese neural network to model the complex relationship between drugs and bioactivity classes, bringing them into a unified latent space. In particular, we introduce a novel representation for the bioactivity classes, called Bio-Prof, and enhance the original bioactivity data sets to tackle data scarcity. These innovative approaches resulted in our model outperforming the previous ones. The evaluation of BioAct-Het is conducted through three distinct strategies: association-based, bioactivity class-based, and compound-based. The association-based strategy utilizes supervised learning classification, while the bioactivity class-based strategy adopts a retrospective study evaluation approach. On the other hand, the compound-based strategy demonstrates similarities to the concept of meta-learning. Furthermore, the model's effectiveness in addressing real-world problems is analyzed through a case study on the application of vancomycin and oseltamivir for COVID-19 treatment as well as molnupiravir's potential efficacy in treating COVID-19 patients. The data and code underlying this article are available on https://github.com/CBRC-lab/BioAct-Het. However, data sets were derived from sources in the public domain.
PubMed: 38046344
DOI: 10.1021/acsomega.3c05778 -
Archives of Virology Jan 2024Genetic reassortment of avian, swine, and human influenza A viruses (IAVs) poses potential pandemic risks. Surveillance is important for influenza pandemic preparedness,...
Genetic reassortment of avian, swine, and human influenza A viruses (IAVs) poses potential pandemic risks. Surveillance is important for influenza pandemic preparedness, but the susceptibility of zoonotic IAVs to the cap-dependent endonuclease inhibitor baloxavir acid (BXA) has not been thoroughly researched. Although an amino acid substitution at position 38 in the polymerase acidic protein (PA/I38) in seasonal IAVs reduces BXA susceptibility, PA polymorphisms at position 38 are rarely seen in zoonotic IAVs. Here, we examined the impact of PA/I38 substitutions on the BXA susceptibility of recombinant A(H5N1) viruses. PA mutants that harbored I38T, F, and M were 48.2-, 24.0-, and 15.5-fold less susceptible, respectively, to BXA than wild-type A(H5N1) but were susceptible to the neuraminidase inhibitor oseltamivir acid and the RNA polymerase inhibitor favipiravir. PA mutants exhibited significantly impaired replicative fitness in Madin-Darby canine kidney cells at 24 h postinfection. In addition, in order to investigate new genetic markers for BXA susceptibility, we screened geographically and temporally distinct IAVs isolated worldwide from birds and pigs. The results showed that BXA exhibited antiviral activity against avian and swine viruses with similar levels to seasonal isolates. All viruses tested in the study lacked the PA/I38 substitution and were susceptible to BXA. Isolates harboring amino acid polymorphisms at positions 20, 24, and 37, which have been implicated in the binding of BXA to the PA endonuclease domain, were also susceptible to BXA. These results suggest that monitoring of the PA/I38 substitution in animal-derived influenza viruses is important for preparedness against zoonotic influenza virus outbreaks.
Topics: Animals; Dogs; Humans; Swine; Influenza A virus; Oxazines; Pyridines; Influenza A Virus, H5N1 Subtype; Thiepins; Influenza, Human; Antiviral Agents; Orthomyxoviridae; Enzyme Inhibitors; Amino Acid Substitution; Endonucleases; Drug Resistance, Viral; Dibenzothiepins; Morpholines; Pyridones; Triazines
PubMed: 38216710
DOI: 10.1007/s00705-023-05958-5 -
Influenza and Other Respiratory Viruses Jul 2023The severe forms of influenza infection requiring intensive care unit (ICU) admission remain a medical challenge due to its high mortality. New H1N1 strains were...
BACKGROUND
The severe forms of influenza infection requiring intensive care unit (ICU) admission remain a medical challenge due to its high mortality. New H1N1 strains were hypothesized to increase mortality. The studies below represent a large series focusing on ICU-admitted influenza patients over the last decade with an emphasis on factors related to death.
METHODS
A retrospective study of patients admitted in ICU for influenza infection over the 2010-2019 period in Réunion Island (a French overseas territory) was conducted. Demographic data, underlying conditions, and therapeutic management were recorded. A univariate analysis was performed to assess factors related to ICU mortality.
RESULTS
Three hundred and fifty adult patients were analyzed. Overall mortality was 25.1%. Factors related to higher mortality were found to be patient age >65, cancer history, need for intubation, early intubation within 48 h after admission, invasive mechanical ventilation (MV), acute respiratory distress syndrome (ARDS), vaso-support drugs, extracorporal oxygenation by membrane (ECMO), dialysis, bacterial coinfection, leucopenia, anemia, and thrombopenia. History of asthma and oseltamivir therapy were correlated with a lower mortality. H1N1 did not impact mortality.
CONCLUSION
Patient's underlying conditions influence hospital admission and secondary ICU admission but were not found to impact ICU mortality except in patients age >65, history of cancer, and bacterial coinfections. Pulmonary involvement was often present, required MV, and often evolved toward ARDS. ICU mortality was strongly related to ARDS severity. We recommend rapid ICU admission of patients with influenza-related pneumonia, management of bacterial coinfection, and early administration of oseltamivir.
Topics: Retrospective Studies; Reunion; Influenza, Human; Intensive Care Units; Hospitalization; Humans; Male; Female; Adult; Middle Aged; Aged; Coinfection; Patient Acuity
PubMed: 37483265
DOI: 10.1111/irv.13168 -
Nutrients Jun 2024Understanding the role of biased taste T1R2/T1R3 G protein-coupled receptors (GPCR) agonists on glycosylated receptor signaling may provide insights into the opposing...
Artificial and Natural Sweeteners Biased T1R2/T1R3 Taste Receptors Transactivate Glycosylated Receptors on Cancer Cells to Induce Epithelial-Mesenchymal Transition of Metastatic Phenotype.
Understanding the role of biased taste T1R2/T1R3 G protein-coupled receptors (GPCR) agonists on glycosylated receptor signaling may provide insights into the opposing effects mediated by artificial and natural sweeteners, particularly in cancer and metastasis. Sweetener-taste GPCRs can be activated by several active states involving either biased agonism, functional selectivity, or ligand-directed signaling. However, there are increasing arrays of sweetener ligands with different degrees of allosteric biased modulation that can vary dramatically in binding- and signaling-specific manners. Here, emerging evidence proposes the involvement of taste GPCRs in a biased GPCR signaling crosstalk involving matrix metalloproteinase-9 (MMP-9) and neuraminidase-1 (Neu-1) activating glycosylated receptors by modifying sialic acids. The findings revealed that most natural and artificial sweeteners significantly activate Neu-1 sialidase in a dose-dependent fashion in RAW-Blue and PANC-1 cells. To confirm this biased GPCR signaling crosstalk, BIM-23127 (neuromedin B receptor inhibitor, MMP-9i (specific MMP-9 inhibitor), and oseltamivir phosphate (specific Neu-1 inhibitor) significantly block sweetener agonist-induced Neu-1 sialidase activity. To assess the effect of artificial and natural sweeteners on the key survival pathways critical for pancreatic cancer progression, we analyzed the expression of epithelial-mesenchymal markers, CD24, ADLH-1, E-cadherin, and N-cadherin in PANC-1 cells, and assess the cellular migration invasiveness in a scratch wound closure assay, and the tunneling nanotubes (TNTs) in staging the migratory intercellular communication. The artificial and natural sweeteners induced metastatic phenotype of PANC-1 pancreatic cancer cells to promote migratory intercellular communication and invasion. The sweeteners also induced the downstream NFκB activation using the secretory alkaline phosphatase (SEAP) assay. These findings elucidate a novel taste T1R2/T1R3 GPCR functional selectivity of a signaling platform in which sweeteners activate downstream signaling, contributing to tumorigenesis and metastasis via a proposed NFκB-induced epigenetic reprogramming modeling.
Topics: Humans; Epithelial-Mesenchymal Transition; Receptors, G-Protein-Coupled; Sweetening Agents; Cell Line, Tumor; Matrix Metalloproteinase 9; Neoplasm Metastasis; Glycosylation; Signal Transduction; Phenotype; Animals; Taste; Cell Movement; Neuraminidase
PubMed: 38931195
DOI: 10.3390/nu16121840 -
Journal of Enzyme Inhibition and... Dec 2023Our previous studies have shown that the introduction of structurally diverse benzyl side chains at the C5-NH position of oseltamivir to occupy 150-cavity contributes to...
Our previous studies have shown that the introduction of structurally diverse benzyl side chains at the C5-NH position of oseltamivir to occupy 150-cavity contributes to the binding affinity with neuraminidase and anti-influenza activity. To obtain broad-spectrum neuraminidase inhibitors, we designed and synthesised a series of novel oseltamivir derivatives bearing different N-heterocycles substituents that have been proved to induce opening of the 150-loop of group-2 neuraminidases. Among them, compound bearing 4-(()-2-methylpyrrolidin-1-yl) benzyl group exhibited antiviral activities similar to or weaker than those of oseltamivir carboxylate against H1N1, H3N2, H5N1, H5N6 and H5N1-H274Y mutant neuraminidases. More encouragingly, displayed nearly 3-fold activity enhancement against H3N2 virus over oseltamivir carboxylate and 2-fold activity enhancement over zanamivir. Molecular docking studies provided insights into the explanation of its broad-spectrum potency against wild-type neuraminidases. Overall, as a promising lead compound, deserves further optimisation by fully considering the ligand induced flexibility of the 150-loop.
Topics: Oseltamivir; Neuraminidase; Molecular Docking Simulation; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H1N1 Subtype; Glycoside Hydrolases
PubMed: 37955306
DOI: 10.1080/14756366.2023.2277135