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Antiviral Therapy 2007Oseltamivir phosphate is a prodrug of oseltamivir carboxylate, a highly specific inhibitor of influenza virus neuraminidases. Given that oseltamivir carboxylate binds to... (Review)
Review
Oseltamivir phosphate is a prodrug of oseltamivir carboxylate, a highly specific inhibitor of influenza virus neuraminidases. Given that oseltamivir carboxylate binds to highly conserved, essential amino acids in the catalytic site of the enzyme, and that the activity of neuraminidase is critical for virus release from infected cells and subsequent virus spread, the drug was expected to have a low propensity to select for viable resistant mutants. Indeed, viruses with neuraminidase (and haemagglutinin) substitutions conferring reduced susceptibility to oseltamivir have been generated with difficulty in vitro, and these mutants generally have reduced infectivity and transmissibility compared with wild-type virus in animal models. Studies of seasonal influenza isolates collected before the introduction of oseltamivir show an absence of naturally occurring resistance. Few resistant mutants have arisen during clinical trials of oseltamivir in seasonal influenza, with cumulative data from all Roche-sponsored studies indicating an incidence of resistance of 0.32% in adults (0.4%, including low-level mutants detected by genotyping alone in mixed virus populations) and 4.1% (5.4%) in children. Higher incidences of resistance were observed in two small Japanese studies, in which children received a different dosing schedule from their Western counterparts. In summary, the overall incidence of influenza virus resistance associated with the seasonal use of oseltamivir is currently low and resistant viruses might be of little clinical significance, except perhaps in immunocompromised individuals. However, continued vigilance, especially of emerging avian H5N1 strains, combined with careful, systematic laboratory-based monitoring, is essential.
Topics: Adolescent; Adult; Aged; Antiviral Agents; Child; Child, Preschool; Drug Resistance, Viral; Enzyme Inhibitors; Humans; Infant; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H2N2 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A virus; Influenza B virus; Influenza, Human; Microbial Sensitivity Tests; Middle Aged; Mutation; Neuraminidase; Oseltamivir
PubMed: 17944268
DOI: No ID Found -
ADMET & DMPK 2019Oseltamivir phosphate (OP, Tamiflu®) is a widely used prodrug for the treatment of influenza viral infections. Orally administered OP is rapidly hydrolyzed by the...
Oseltamivir phosphate (OP, Tamiflu®) is a widely used prodrug for the treatment of influenza viral infections. Orally administered OP is rapidly hydrolyzed by the carboxylesterases in animals to oseltamivir carboxylate (OC), a potent influenza virus neuraminidase inhibitor. The goals of this study were to develop and validate a physiologically-based pharmacokinetic (PBPK) model of OP/OC in rats and humans, and to predict the internal tissue doses for OP and OC in humans after receiving OP orally. To this end, a PBPK model of OP/OC was first developed in the rat, which was then scaled up to humans by replacing the physiological and biochemical parameters with human-specific values. The proposed PBPK model consisted of an OP and an OC sub-models each containing nine first-order, flow-limited tissue/organ compartments. OP metabolism to OC was assumed to carry out mainly by hepatic carboxylesterases although extra-hepatic metabolism also occurred especially in the plasma. The PBPK model was developed and validated by experimental data from our laboratories and from the literature. The proposed PBPK model accurately predicted the pharmacokinetic behavior of OP and OC in humans and rats after receiving a single or multiple doses of OP orally or an OC dose i.v. The PBPK model was used to predict the internal tissue doses of OP and OC in a hypothetical human after receiving the recommended dose of 75 mg/kg OP b.i.d. for 6 days. Steady-state OC concentrations in the plasma and major organs such as the lung and the brain were higher than the minimum in vitro IC50 reported for H1N1 influenza virus neuraminidase, confirming OP is an effective, anti-viral agent. OP side-effects in the gastrointestinal tract and brain of humans were explainable by the tissue doses found in these organs. The PBPK model provides a quantitative tool to evaluate the relationship between an externally applied dose of OP and the internal tissue doses in humans. As such the model can be used to adjust the dose regimens for adult patients in disease states e.g., renal failure and liver damage.
PubMed: 35350745
DOI: 10.5599/admet.628 -
Journal of Pharmaceutical Sciences Jun 2013The objective of the present work was to evaluate and characterize a pediatric-friendly formulation of a bitter tasting drug, oseltamivir phosphate (drug). Amberlite...
The objective of the present work was to evaluate and characterize a pediatric-friendly formulation of a bitter tasting drug, oseltamivir phosphate (drug). Amberlite IRP64 (resin) was used to make ionic complexes for masking its bitterness. Complexes of four drug-to-resin ratios, 1:1, 1:2, 1:4, and 1:6 (w/w), were prepared and characterized. At buccal pH of 6.8, drug-resin complexes of 1:1, 1:2, 1:4, and 1:6 ratios released 42.13%, 23.26%, 4.13%, and 14.94%, respectively, of loaded drug after 20 s. However, at stomach pH of 1.2 (0.1 N HCl), 61.96%, 70.18%, 85.88%, and 91.42% of drug was released from the same complexes in 6 min. Near-infrared (NIR) chemical imaging of the complexes showed homogeneous distribution of drug in the resin. Chemometric partial least squares model using NIR data of the drug showed a high correlation between calibration and predicted data (R(2) > 0.998). Overall, these results indicated the complex formation between drug and resin. The pH dependence of drug release from these complexes could minimize drug release in the mouth, whereas immediately releasing it in the stomach. Electronic tongue used to evaluate taste indicated that conductivity taste signals were different from control, suggesting taste masking of the drug.
Topics: Antiviral Agents; Child; Drug Carriers; Humans; Hydrogen-Ion Concentration; Ions; Oseltamivir; Resins, Synthetic; Spectroscopy, Fourier Transform Infrared; Spectroscopy, Near-Infrared; Taste; Tongue
PubMed: 23559456
DOI: 10.1002/jps.23518 -
Platelets 2015The management of chronic immune thrombocytopenia (ITP) remains to be a challenge. Oseltamivir phosphate is a sialidase inhibitor agent used to treat influenza in the...
The management of chronic immune thrombocytopenia (ITP) remains to be a challenge. Oseltamivir phosphate is a sialidase inhibitor agent used to treat influenza in the conventional sense. At present, we demonstrate for the first time that an adult chronic ITP patient with anti-GP Ib/IX autoantibody, who was resistant to corticosteroids, IVIG, recombinant human thrombopoietin, rituximab, danazol and vindesine, but was successfully treated with oseltamivir phosphate. Through flow cytometric analysis of β-galactose and β-GlcNAc exposure on platelet surfaces, we showed that oseltamivir phosphate could reduce the desialylation level of platelet glycoproteins in ITP patient. The substantial alleviation of thrombocytopenia in this case, though not leading to conclusions, lays a foundation for a novel approach for the treatment of ITP.
Topics: Aged; Autoantibodies; Humans; Male; Oseltamivir; Platelet Count; Platelet Glycoprotein GPIb-IX Complex; Purpura, Thrombocytopenic, Idiopathic; Treatment Outcome
PubMed: 25166956
DOI: 10.3109/09537104.2014.948838 -
Cancers Jul 2022Metastatic pancreatic cancer has an invariably fatal outcome, with an estimated median progression-free survival of approximately six months employing our best...
Repositioning of Old Drugs for Novel Cancer Therapies: Continuous Therapeutic Perfusion of Aspirin and Oseltamivir Phosphate with Gemcitabine Treatment Disables Tumor Progression, Chemoresistance, and Metastases.
Metastatic pancreatic cancer has an invariably fatal outcome, with an estimated median progression-free survival of approximately six months employing our best combination chemotherapeutic regimens. Once drug resistance develops, manifested by increased primary tumor size and new and growing metastases, patients often die rapidly from their disease. Emerging evidence indicates that chemotherapy may contribute to the development of drug resistance through the upregulation of epithelial-mesenchymal transition (EMT) pathways and subsequent cancer stem cell (CSC) enrichment. Neuraminidase-1 (Neu-1) regulates the activation of several receptor tyrosine kinases implicated in EMT induction, angiogenesis, and cellular proliferation. Here, continuous therapeutic targeting of Neu-1 using parenteral perfusion of oseltamivir phosphate (OP) and aspirin (ASA) with gemcitabine (GEM) treatment significantly disrupts tumor progression, critical compensatory signaling mechanisms, EMT program, CSC, and metastases in a preclinical mouse model of human pancreatic cancer. ASA- and OP-treated xenotumors significantly inhibited the metastatic potential when transferred into animals.
PubMed: 35892853
DOI: 10.3390/cancers14153595 -
Journal of Microbiology (Seoul, Korea) Dec 2017Influenza viruses are major human respiratory pathogens that cause high morbidity and mortality worldwide. Currently, prophylactic vaccines and therapeutic antiviral... (Comparative Study)
Comparative Study
Influenza viruses are major human respiratory pathogens that cause high morbidity and mortality worldwide. Currently, prophylactic vaccines and therapeutic antiviral agents are used to prevent and control influenza virus infection. Oseltamivir free base (OSV-FB), a modified generic antiviral drug of Tamiflu (oseltamivir phosphate, OSV-P), was launched in the Republic of Korea last year. Here, we examine the bioequivalence of these two compounds by assessing their antiviral efficacy in infected cells and in a mouse model. It was observed that both antivirals showed comparable efficacy against 11 different influenza A and B viruses in vitro. Moreover, in mice infected with influenza A virus (mouse-adapted A/Puerto Rico/8/34), they showed a dose-dependent therapeutic activity and alleviated infection-mediated reductions in body weight, leading to significantly better survival. There was histopathological disappearance of virus-induced inflammatory cell infiltration of the lung after oral treatment with either antiviral agent (at 10 mg/kg). Pharmacokinetic analysis also exhibited similar plasma concentrations of the active drug, oseltamivir carboxylate, metabolised from both OSV-B and OSV-P. This is the first report showing bioequivalence of OSV-FB to its phosphate salt form in the mouse system. The free base drug has some beneficial points including simple drug formulation process and reduced risk of undesirable cation-phosphate precipitation within solution. The long term stability of OSV-FB requires further monitoring when it is provided as a national stock in readiness for an influenza pandemic.
Topics: Animals; Antiviral Agents; Female; Humans; Influenza A virus; Influenza B virus; Influenza, Human; Lung; Mice; Mice, Inbred BALB C; Oseltamivir; Therapeutic Equivalency
PubMed: 29214495
DOI: 10.1007/s12275-017-7371-x -
Journal of Chromatography. B,... Jun 2018Oseltamivir phosphate (OP) is the first line therapy for influenza, and its primary metabolite oseltamivir carboxylate (OC) is the active agent via inhibition of...
Oseltamivir phosphate (OP) is the first line therapy for influenza, and its primary metabolite oseltamivir carboxylate (OC) is the active agent via inhibition of neuraminidase of influenza virus. Dosages of OP and OC might affect human causing nausea and vomiting and it is therefore necessary to evaluate their toxicity and safety. The separation system: liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a powerful technique to monitor OP and OC. However, quantification of OP and OC needs isotopic analogs as internal standards to monitor the stability of the sample pretreatment procedures and instruments. In this study, we demonstrated a modified method (i.e., reductive amination) to synthesize OP and OC deuterated and hydrogenated analogs as internal standards (ISs) and for illustration of calibration curves, respectively. This modification allowed to overcome ISs selection and to enhance the signal intensities via high yield reductive amination in MS detection. We utilized the multiple reaction monitoring (MRM) mode to target m/z values of precursor and product ions. N-dimethylated OP and N-dimethylated OC showed linearity ranging from 1 to 1000 ng/mL with coefficient of determination (R) values of 0.9995 and 0.9999, respectively. Additionally, the relative standard deviations (RSD) of intra-day ranged from 0.3% to 5.2%, and the RSD of inter-day ranged from 2.0% to 18.8%, respectively. This quantitative method utilized spiked OP and OC at low (20 ng/mL), intermediate (100 ng/mL), and high (500 ng/mL) concentrations in human serum samples. The average recoveries for OP and OC were 84.6%-107.7% and 94.9%-98.5%, respectively.
Topics: Chromatography, High Pressure Liquid; Humans; Limit of Detection; Linear Models; Oseltamivir; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 29702353
DOI: 10.1016/j.jchromb.2018.03.040 -
Acta Virologica 2022Oseltamivir phosphate (OS) is currently the most frequently used influenza antiviral drug. It moderates the course of influenza virus type A (IAV) infection, however,...
Oseltamivir phosphate (OS) is currently the most frequently used influenza antiviral drug. It moderates the course of influenza virus type A (IAV) infection, however, its impact on the induction of virus-neutralizing antibodies (VNAbs) is not understood in details. Here, we examined the influence of low (10 mg/kg) or high (60 mg/kg) doses of OS on the viral titer in lungs of BALB/c mice infected with 0.5 LD50 of IAV and on the level of VNAbs. Prophylactic application of OS (6 h before the infection) delayed the increase of viral titer in lungs with a lower peak in comparison to non-treated control mice. After therapeutic OS application (44 h after the infection), maximum of virus titer did not significantly change. However, the induction of VNAbs strongly decreased, to 16.7%-18.1% of the control, after preventive application of high OS dose. A minimal decrease of VNAbs titers was observed in groups of mice treated with low dose of OS applied therapeutically. They lowered to 91.1% / 14 or to 94.1% / 21 days post infection (p.i.) of VNAbs titers of non-treated control mice. In all other groups, levels of VNAbs titers dropped to 26.5-53.7% of those of non-treated mice. It should be noted that VNAbs titers were in direct proportion to maximal virus titers in mouse lungs of corresponding groups. In summary, after OS application the clinical symptoms of the disease were milder or non-observable in all OS-treated groups, but the lowering of VNAbs titers was dependent on the OS dose and interval between drug app-lication and the start of infection. Keywords: influenza A virus; Oseltamivir; prophylactic treatment; therapeutic treatment; virus-neutralizing antibodies.
Topics: Animals; Antibodies, Neutralizing; Antiviral Agents; Humans; Influenza A virus; Influenza, Human; Lung; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections; Oseltamivir; Phosphates
PubMed: 36029093
DOI: 10.4149/av_2022_312 -
Cancers Mar 2022Resistance to chemotherapeutics and high metastatic rates contribute to the abysmal survival rate in patients with pancreatic cancer. An alternate approach for treating...
Next Generation of Cancer Drug Repurposing: Therapeutic Combination of Aspirin and Oseltamivir Phosphate Potentiates Gemcitabine to Disable Key Survival Pathways Critical for Pancreatic Cancer Progression.
Resistance to chemotherapeutics and high metastatic rates contribute to the abysmal survival rate in patients with pancreatic cancer. An alternate approach for treating human pancreatic cancer involves repurposing the anti-inflammatory drug, aspirin (ASA), with oseltamivir phosphate (OP) in combination with the standard chemotherapeutic agent, gemcitabine (GEM). The question is whether treatment with ASA and OP can sensitize cancer cells to the cytotoxicity induced by GEM and limit the development of chemoresistance. To assess the key survival pathways critical for pancreatic cancer progression, we used the AlamarBlue cytotoxicity assay to determine the cell viability and combination index for the drug combinations, flow cytometric analysis of annexin V apoptosis assay to detect apoptotic and necrotic cells, fluorometric QCM™ chemotaxis migration assay to assess cellular migration, fluorometric extracellular matrix (ECM) cell adhesion array kit to assess the expression of the ECM proteins, scratch wound assay using the 96-well WoundMaker™, and the methylcellulose clonogenic assay to assess clonogenic potential. The combination of ASA and OP with GEM significantly upended MiaPaCa-2 and PANC-1 pancreatic cancer cell viability, clonogenic potential, expression of critical extracellular matrix proteins, migration, and promoted apoptosis. ASA in combination with OP significantly improves the effectiveness of GEM in the treatment of pancreatic cancer and disables key survival pathways critical to disease progression.
PubMed: 35326525
DOI: 10.3390/cancers14061374 -
MBio Oct 2019The 1918 influenza virus, subtype H1N1, was the causative agent of the most devastating pandemic in the history of infectious diseases. studies have confirmed that...
The 1918 influenza virus, subtype H1N1, was the causative agent of the most devastating pandemic in the history of infectious diseases. studies have confirmed that extreme virulence is an inherent property of this virus. Here, we utilized the macaque model for evaluating the efficacy of oseltamivir phosphate against the fully reconstructed 1918 influenza virus in a highly susceptible and relevant disease model. Our findings demonstrate that oseltamivir phosphate is effective in preventing severe disease in macaques but vulnerable to virus escape through emergence of resistant mutants, especially if given in a treatment regimen. Nevertheless, we conclude that oseltamivir would be highly beneficial to reduce the morbidity and mortality rates caused by a highly pathogenic influenza virus although it would be predicted that resistance would likely emerge with sustained use of the drug. Oseltamivir phosphate is used as a first line of defense in the event of an influenza pandemic prior to vaccine administration. Treatment failure through selection and replication of drug-resistant viruses is a known complication in the field and was also demonstrated in our study with spread of resistant 1918 influenza virus in multiple respiratory tissues. This emphasizes the importance of early treatment and the possibility that noncompliance may exacerbate treatment effectiveness. It also demonstrates the importance of implementing combination therapy and vaccination strategies as soon as possible in a pandemic situation.
Topics: Animals; Influenza A Virus, H1N1 Subtype; Macaca; Orthomyxoviridae Infections; Oseltamivir
PubMed: 31641086
DOI: 10.1128/mBio.02059-19