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Antimicrobial Agents and Chemotherapy Jun 2019The aim of this study was to investigate the pharmacokinetics of oseltamivir phosphate, a prodrug, and its active moiety in plasma and lung after its nebulization and...
The aim of this study was to investigate the pharmacokinetics of oseltamivir phosphate, a prodrug, and its active moiety in plasma and lung after its nebulization and intravenous administration in rats. Only 2% of prodrug was converted into active moiety presystematically, attesting to a low advantage of oseltamivir phosphate nebulization, suggesting that oseltamivir phosphate nebulization is not a good option to obtain a high exposure of the active moiety at the infection site within lung.
Topics: Administration, Intravenous; Animals; Male; Oseltamivir; Phosphates; Prodrugs; Rats; Rats, Sprague-Dawley
PubMed: 30962337
DOI: 10.1128/AAC.00074-19 -
Influenza A/H3N2 virus infection in immunocompromised ferrets and emergence of antiviral resistance.PloS One 2018Influenza viruses can cause severe life threatening infections in high-risk patients, including young children, the elderly and patients with compromised immunity due to...
Influenza viruses can cause severe life threatening infections in high-risk patients, including young children, the elderly and patients with compromised immunity due to underlying medical conditions or immunosuppressive treatment. The impaired immunity of these patients causes prolonged virus infection and combined with antiviral treatment facilitates the emergence of viruses with resistance mutations. The diverse nature of their immune status makes them a challenging group to study the impact of influenza virus infection and the efficacy of antiviral therapy. Immunocompromised ferrets may represent a suitable animal model to assess influenza virus infection and antiviral treatment strategies in immunocompromised hosts. Here, ferrets were given a daily oral solution of mycophenolate mofetil, tacrolimus and prednisolone sodium phosphate to suppress their immune system. Groups of immunocompromised and immunocompetent ferrets were inoculated with an A/H3N2 influenza virus and were subsequently treated with Oseltamivir or left untreated. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was performed on the throat and nose specimens to study virus replication during the course of infection. All immunocompromised ferrets had prolonged presence of viral RNA and a higher total amount of virus shedding compared to the immunocompetent ferrets. Although Oseltamivir reduced the total amount of virus shedding from the nose and throat of treated ferrets, it also resulted in the emergence of the neuraminidase R292K resistance substitution in all these animals, as determined by mutation specific RT-PCR and next-generation sequencing. No additional mutations that could be associated with the emergence of the R292K resistance mutation were detected. The immunocompromised ferret model can be used to study A/H3N2 virus shedding and is a promising model to study new antiviral strategies and the emergence of antiviral resistance in immunocompromised hosts.
Topics: Animals; Antiviral Agents; Drug Resistance, Viral; Ferrets; Immunocompromised Host; Influenza A Virus, H3N2 Subtype; Orthomyxoviridae Infections; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 30024940
DOI: 10.1371/journal.pone.0200849 -
Scientific Reports Apr 2023A green, rapid, and simple RP-UPLC method was developed and optimized by full factorial design for the simultaneous separation of oseltamivir phosphate, daclatasivir...
A green, rapid, and simple RP-UPLC method was developed and optimized by full factorial design for the simultaneous separation of oseltamivir phosphate, daclatasivir dihydrochloride, and remdesivir, with dexamethasone as a co-administered drug. The separation was established on a UPLC column BEH C 1.7 µm (2.1 × 100.0 mm) connected with a UPLC pre-column BEH 1.7 µm (2.1 × 5.0 mm) at 25 °C with an injection volume of 10 µL. The detector (PDA) was set at 239 nm. The mobile phase consisted of methanol and ammonium acetate (8.1818 mM) in a ratio of 75.7: 24.3 (v/v). The flow rate was set at 0.048 mL min. The overall separation time was 9.5 min. The retention times of oseltamivir phosphate, dexamethasone, daclatasivir dihydrochloride, and remdesivir were 6.323 ± 0.145, 7.166 ± 0.036, 8.078 ± 0.124, and 8.572 ± 0.166 min (eight replicates), respectively. The proposed method demonstrated linearity in the ranges of 10.0-500.0 (ng mL) and 0.5-30.0 (µg mL) for oseltamivir phosphate, 50.0-5000.0 (ng mL) for dexamethasone, 25.0-1000.0 (ng mL) and 0.5-25.0 (µg mL) for daclatasvir dihydrochlorde, and 10.0-500.0 (ng mL) and 0.5-30.0 (µg mL) for remdesivir. The coefficients of determination (R) were greater than 0.9999, with percentage recoveries greater than 99.5% for each drug. The limits of quantitation were 6.4, 1.8, 7.8, and 1.6 ng mL, and the limits of detection were 1.9, 0.5, 2.0, and 0.5 ng mL for oseltamivir phosphate, dexamethasone, daclatasivir dihydrochloride, and remdesivir, respectively. The proposed method was highly precise, as indicated by the low percentage of relative standard deviation values of less than 1.2% for each drug. The average content and uniformity of dosage units in the studied drugs' dosage forms were determined. The average contents of oseltamivir phosphate, dexamethasone, daclatasivir dihydrochloride, and remdesivir were nearly 93%, 102%, 99%, and 95%, respectively, while the uniformity of dosage unit values were nearly 92%, 102%, 101%, and 97%. Two novel methods were established in this work. The first method was used to assess the stability of standard solutions. This novel method was based on the slope of regression equations. The second was to evaluate the excipient's interference using an innovative instrumental standard addition method. The novel instrumental standard addition method was performed using the UPLC instrument program. It was more accurate, sensitive, time-saving, economical, and eco-friendly than the classic standard addition method. The results showed that the proposed method can estimate the tested drugs' concentrations without interference from their dosage form excipients. According to the Eco-score (more than 75), the Green Analytical Procedure Index (GAPI), and the AGREE criteria (total score of 0.77), the suggested method was considered eco-friendly.
Topics: Humans; Chromatography, High Pressure Liquid; Oseltamivir; COVID-19; Dexamethasone; Phosphates
PubMed: 37016018
DOI: 10.1038/s41598-023-32405-x -
Scientific Reports Nov 2018A lateral flow immunochromatographic strip test (LFIST) based on a competitive format was developed for rapid and sensitive on-site detection of oseltamivir phosphate...
A lateral flow immunochromatographic strip test (LFIST) based on a competitive format was developed for rapid and sensitive on-site detection of oseltamivir phosphate (OP) residues in poultry product. The sensitivity (half inhibitory concentration, IC) of the LFIST in the detection of egg and chicken meat samples was confirmed to be 2.56 and 2.63 µg/kg, and the limit detection (LOD) value were 0.43 and 0.42 µg/kg, respectively. For intra-assay and inter-assay reproducibility, recoveries of OP spiked samples ranged between 82.8% and 91.2% with coefficients of variations (CV) less than 5.67% (intra-assay) and 6.52% (inter-assay). The performance of LFIST was comparable to high-performance liquid chromatography (HPLC) in a parallel testing of egg samples and chicken samples. LFIST takes less than 5 minutes, eliminates the dependency on professional personnel, and thus can be used as a surveillance tool for on-site detection of OP residues.
Topics: Animals; Chickens; Chromatography, High Pressure Liquid; Eggs; Enzyme-Linked Immunosorbent Assay; Limit of Detection; Meat; Molecular Structure; Oseltamivir; Reagent Strips
PubMed: 30420605
DOI: 10.1038/s41598-018-35080-5 -
Viruses Nov 2023Influenza remains a worldwide health concern. Antiviral drugs are considered as one of the useful options for its prevention as a complementary measure to vaccination....
Influenza remains a worldwide health concern. Antiviral drugs are considered as one of the useful options for its prevention as a complementary measure to vaccination. Baloxavir acid selectively inhibits the cap-dependent endonuclease of influenza viruses and exhibits marked viral titre reduction in patients. Here, we describe the prophylactic potency of baloxavir acid against lethal infection with influenza A and B viruses in mice. BALB/c mice were subcutaneously administered once with baloxavir acid suspension, or orally administered once daily for 10 days with oseltamivir phosphate solution at human relevant doses. Next, the mice were intranasally inoculated with A/PR/8/34 (H1N1) or B/Hong Kong/5/72 strain at 24 to 96 h after the initial dosing. Prophylactic treatment with the antiviral drugs significantly reduced the lung viral titres and prolonged survival time. In particular, baloxavir acid showed a greater suppressive effect on lung viral titres compared to oseltamivir phosphate. In this model, baloxavir acid maintained significant prophylactic effects against influenza A and B virus infections when the plasma concentration at the time of infection was at least 0.88 and 3.58 ng/mL, respectively. The significant prophylactic efficacy observed in our mouse model suggests the potential utility of baloxavir marboxil for prophylaxis against influenza in humans.
Topics: Humans; Animals; Mice; Influenza, Human; Oseltamivir; Herpesvirus 1, Cercopithecine; Influenza A Virus, H1N1 Subtype; Oxazines; Pyridines; Thiepins; Antiviral Agents; Mice, Inbred BALB C; Phosphates
PubMed: 38005940
DOI: 10.3390/v15112264 -
Oncotarget Oct 2016Multicellular tumor spheroids (MTS) have been at the forefront of cancer research, designed to mimic tumor-like developmental patterns in vitro. Tumor growth in vivo is...
Multicellular tumor spheroids (MTS) have been at the forefront of cancer research, designed to mimic tumor-like developmental patterns in vitro. Tumor growth in vivo is highly influenced by aberrant cell surface-specific sialoglycan structures on glycoproteins. Aberrant sialoglycan patterns that facilitate MTS formation are not well defined. Matrix-free spheroids from breast MCF-7 and pancreatic PANC1 cancer cell lines and their respective tamoxifen (TMX) and gemcitabine (Gem) resistant variants were generated using the RGD platform of cyclic Arg-Gly-Asp-D-Phe-Lys peptide modified with 4-carboxybutyl-triphenylphosphonium bromide (cyclo-RGDfK (TPP)). MCF-7 and MCF-7 TMX cells formed tight spheroids both in the classical agarose-and RGD-based platforms while all PANC1 cells formed loose aggregates. Using lectin histochemistry staining, sialidase assay, neuraminidase (Vibrio cholerae) and oseltamivir phosphate (OP) neuraminidase inhibitor treatments, MCF-7 and PANC1 cells and their drug-resistant variants expressed different sialic acid (SA) content on their cell surfaces. α-2,3- and α-2,6-sialic acid surface residues facilitated spheroid formation under cyclo-RGDfK(TPP)-induced self-assembly. Pretreatment with α-2,3- SA specific Maackia amurensis (MAL-II) lectin, α-2,6-SA specific Sambucus nigra (SNA) lectin, and exogenous α-2,6-SA specific neuraminidase (Vibrio cholerae) dose-dependently reduced spheroid volume. OP enhanced cell aggregation and compaction forming spheroids. PANC1 and MDA-MB231 xenograft tumors from untreated and OP-treated RAGxCγ double mutant mice expressed significantly higher levels of α-2,3- SA over α-2,6-SA. MCF-7 spheroids also expressed a high α-2,3-SA to α-2,6-SA ratio. These results suggest that the relative levels of specific sialoglycan structures on the cell surface correlate with the ability of cancer cells to form avascular multicellular tumor spheroids and in vivo xenograft tumors.
Topics: Animals; Breast Neoplasms; Cell Adhesion; Cell Movement; Cell Proliferation; Female; Glycoproteins; Humans; Mice; N-Acetylneuraminic Acid; Pancreatic Neoplasms; Peptides, Cyclic; Spheroids, Cellular; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 27608845
DOI: 10.18632/oncotarget.11868 -
Chinese Journal of Natural Medicines Sep 2019Ge Gen Decoction (GGD), a Traditional Chinese Medicine prescription, is mainly used to treat infectious respiratory diseases and can relieve the symptoms of influenza A...
Ge Gen Decoction (GGD), a Traditional Chinese Medicine prescription, is mainly used to treat infectious respiratory diseases and can relieve the symptoms of influenza A virus (IAV) infection. However, the underlying mechanism of GGD against IAV infection remains unclear. In this study, we found that GGD had moderate anti-IAV activity in vitro. GGD was more effective when given before the viral infection and targeted the viral attachment and replication stages rather than the internalization stage. In vivo, GGD treatment reduced thevirus titers of lung tissue significantly and improved the survival rate, lung index, and pulmonary histopathological changes in H1N1-infected mice. We observed the changes in several key immuno-related indexes in GGD administrated H1N1-infected mice with anti-IAV drug oseltamivir phosphate as the control. GGD treatment decreased the expression of TNF-α and improved Th1/Th2 immune balance to reduce the excessive immune response in H1N1-infected mice. Besides, the expression of the toll-like receptor 7 signaling pathway in H1N1-infected mice decreased after GGD treatment. Our results showed that GGD has anti-IAV activity and can modulate the immune system to relieve lung inflammation.
Topics: Animals; Antiviral Agents; Cytokines; Dogs; Drugs, Chinese Herbal; Female; Influenza A Virus, H1N1 Subtype; Influenza A virus; Lung; Madin Darby Canine Kidney Cells; Membrane Glycoproteins; Mice, Inbred ICR; Orthomyxoviridae Infections; Oseltamivir; Signal Transduction; Th1-Th2 Balance; Toll-Like Receptor 7; Virus Attachment; Virus Replication
PubMed: 31526500
DOI: 10.1016/S1875-5364(19)30079-2 -
Oncotarget Feb 2018Pickering emulsions are colloidal dispersions stabilized by particles that either migrate to, or are formed at, the oil-water interface during emulsification. Here, we...
Pickering emulsions are colloidal dispersions stabilized by particles that either migrate to, or are formed at, the oil-water interface during emulsification. Here, we fabricated and characterized Pickering water-in-oil emulsions where molten glycerol monostearate crystallized at the surface of micron-sized water droplets and formed protective solid shells. We tested this emulsion as a reservoir delivery platform for the sustained release of low molecular weight hydrophilic molecules including sodium chloride (NaCl) and sodium citrate as model compounds, and the therapeutic oseltamivir phosphate (OP), the delivery of which was the ultimate goal of this research. The objective was to achieve long-term (30-day) release of challenging to encapsulate actives and ultimately demonstrate the sustained release of OP for 20-30 days from an injectable formulation. OP was used because of its anticancer properties targeting mammalian neuraminidase 1 (Neu1) involved in multistage tumorigenesis. All actives including OP encapsulated in Pickering emulsions displayed a near linear release profile over 30 days. It was demonstrated that the release could be modulated by the addition of a second, competing surfactant sorbitan monooleate, Span 80, to the emulsion at levels above its critical micelle concentration. OP released from the emulsions significantly reduced cell viability in the human PANC-1 pancreatic cancer cell line for up to 30 days. The findings from this study indicate a simple, potentially injectable formulation and method that is easily upscaled resulting in a stable product with the potential to fully retain small hydrophilic molecules/drugs for sustained, near linear release over days, weeks, and potentially months.
PubMed: 29560107
DOI: 10.18632/oncotarget.24339 -
The Journal of Antimicrobial... Mar 2019Baloxavir marboxil (formerly S-033188) is a first-in-class, orally available, cap-dependent endonuclease inhibitor licensed in Japan and the USA for the treatment of...
OBJECTIVES
Baloxavir marboxil (formerly S-033188) is a first-in-class, orally available, cap-dependent endonuclease inhibitor licensed in Japan and the USA for the treatment of influenza virus infection. We evaluated the efficacy of delayed oral treatment with baloxavir marboxil in combination with a neuraminidase inhibitor in a mouse model of lethal influenza virus infection.
METHODS
The inhibitory potency of baloxavir acid (the active form of baloxavir marboxil) in combination with neuraminidase inhibitors was tested in vitro. The therapeutic effects of baloxavir marboxil and oseltamivir phosphate, or combinations thereof, were evaluated in mice lethally infected with influenza virus A/PR/8/34; treatments started 96 h post-infection.
RESULTS
Combinations of baloxavir acid and neuraminidase inhibitor exhibited synergistic potency against viral replication by means of inhibition of cytopathic effects in vitro. In mice, baloxavir marboxil monotherapy (15 or 50 mg/kg twice daily) significantly and dose-dependently reduced virus titre 24 h after administration and completely prevented mortality, whereas oseltamivir phosphate treatments were not as effective. In this model, a suboptimal dose of baloxavir marboxil (0.5 mg/kg twice daily) in combination with oseltamivir phosphate provided additional efficacy compared with monotherapy in terms of virus-induced mortality, elevation of cytokine/chemokine levels and pathological changes in the lung.
CONCLUSIONS
Baloxavir marboxil monotherapy with 96 h-delayed oral dosing achieved drastic reductions in virus titre, inflammatory response and mortality in a mouse model. Combination treatment with baloxavir acid and oseltamivir acid in vitro and baloxavir marboxil and oseltamivir phosphate in mice produced synergistic responses against influenza virus infections, suggesting that treating humans with the combination may be beneficial.
Topics: Administration, Oral; Animals; Antiviral Agents; Dibenzothiepins; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Influenza A virus; Mice, Inbred BALB C; Morpholines; Orthomyxoviridae Infections; Oseltamivir; Oxazines; Pyridines; Pyridones; Survival Analysis; Thiepins; Treatment Outcome; Triazines; United States
PubMed: 30476172
DOI: 10.1093/jac/dky462 -
Journal of Neurovirology Feb 2021As the SARS-COV-2 becomes a global pandemic, many researchers have a concern about the long COVID-19 complications. Chronic fatigue syndrome/myalgic encephalomyelitis...
As the SARS-COV-2 becomes a global pandemic, many researchers have a concern about the long COVID-19 complications. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a persistent, debilitating, and unexplained fatigue disorder. We investigated psychological morbidities such as CFS and post-traumatic stress disorder (PTSD) among survivors of COVID-19 over 6 months. All COVID-19 survivors from the university-affiliated hospital of Tehran, Iran, were assessed 6 months after infection onset by a previously validated questionnaire based on the Fukuda guidelines for CFS/EM and DSM-5 Checklist for PTSD (The Post-traumatic Stress Disorder Checklist for DSM-5 or PCL-5) to determine the presence of stress disorder and chronic fatigue problems. A total of 120 patients were enrolled. The prevalence rate of fatigue symptoms was 17.5%. Twelve (10%) screened positive for chronic idiopathic fatigue (CIF), 6 (5%) for CFS-like with insufficient fatigue syndrome (CFSWIFS), and 3 (2.5%) for CFS. The mean total scores in PCL-5 were 9.27 ± 10.76 (range:0-44), and the prevalence rate of PTSD was 5.8%. There was no significant association after adjusting between CFS and PTSD, gender, comorbidities, and chloroquine phosphate administration. The obtained data revealed the prevalence of CFS among patients with COVID-19, which is almost similar to CFS prevalence in the general population. Moreover, PTSD in patients with COVID-19 is not associated with the increased risk of CFS. Our study suggested that medical institutions should pay attention to the psychological consequences of the COVID-19 outbreak.
Topics: Adult; Aged; Antiviral Agents; COVID-19; Cough; Dementia; Drug Combinations; Dyspnea; Fatigue Syndrome, Chronic; Female; Fever; Humans; Hydroxychloroquine; Lopinavir; Male; Middle Aged; Oseltamivir; Research Design; Ritonavir; SARS-CoV-2; Severity of Illness Index; Stress Disorders, Post-Traumatic; Surveys and Questionnaires; Survivors; COVID-19 Drug Treatment
PubMed: 33528827
DOI: 10.1007/s13365-021-00949-1