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Bioorganic Chemistry Dec 2022Triptolide (TP) is a major active compound derived from the traditional Chinese medicine Tripterygium wilfordii. TP has been reported to inhibit the infection of HIV and...
Triptolide (TP) is a major active compound derived from the traditional Chinese medicine Tripterygium wilfordii. TP has been reported to inhibit the infection of HIV and a few other viruses. However, the antiviral spectrum and the underlying mechanisms of TP are incompletely defined. TP derivatives were designed, synthesized, and evaluated for anti-influenza activity against the influenza A virus in this study. All of them exhibited activities against oseltamivir sensitive influenza A/WSN/33 virus (H1N1) and oseltamivir resistant influenza A/PR/8/33 virus (H1N1) with low cytotoxicity in vitro. In our present study, TP derivatives probably suppressed influenza virus replication through inhibiting ribonucleoprotein complex nucleus export of influenza A virus by binding with viral nucleoprotein. Moreover, TP derivatives downregulated influenza A virus-induced macrophage cytokine storm in a dose-dependent manner, through inhibiting nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) and NOD-like receptor protein 3 (NLRP3) inflammasome signaling. Taken together, TP derivatives suppressed influenza A virus replication by directly targeting NP and regulating innate immune responses induced by influenza A virus infection, which suggested that TP derivatives might be prospective candidates for potent antivirals.
Topics: Humans; Nucleoproteins; Oseltamivir; Influenza A Virus, H1N1 Subtype; Influenza A virus; Influenza, Human; Antiviral Agents
PubMed: 36067538
DOI: 10.1016/j.bioorg.2022.106118 -
Birth Defects Research Nov 2019Influenza during pregnancy contributes to maternal morbidity and mortality. Neuraminidase inhibitors, including oseltamivir, are recommended for treating women with...
BACKGROUND
Influenza during pregnancy contributes to maternal morbidity and mortality. Neuraminidase inhibitors, including oseltamivir, are recommended for treating women with influenza during pregnancy.
METHODS
Data from the Slone Birth Defects Study from 2009 to 2015 were used to investigate associations between oseltamivir and specific birth defects. We classified exposures according to timing in pregnancy and examined 52 and 16 defects with early and potential late pregnancy etiology, respectively; we calculated crude odds ratios (ORs) and 95% confidence intervals (CIs) for defects with three or more exposures.
RESULTS
Among 8,379 cases and 4,190 nonmalformed controls, we identified 79 and 42 oseltamivir exposures, respectively. The majority of defects had no exposures. ORs were elevated for several defects, but the CI excluded the null only for intestinal malrotation (OR: 10.7 [1.8, 45.2]; three exposures).
CONCLUSIONS
Largely null findings for specific defects are reassuring. The association with intestinal malrotation, while unstable, warrants further investigation.
Topics: Adult; Case-Control Studies; Congenital Abnormalities; Female; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Odds Ratio; Oseltamivir; Pregnancy; Pregnancy Complications, Infectious; Prenatal Exposure Delayed Effects; Young Adult
PubMed: 31397115
DOI: 10.1002/bdr2.1563 -
Clinical Drug Investigation Aug 2021Influenza-like illness (ILI) leads to a substantial disease burden every winter in Europe; however, oseltamivir is not frequently prescribed to ILI patients in the... (Randomized Controlled Trial)
Randomized Controlled Trial
Direct and Indirect Costs of Influenza-Like Illness Treated with and Without Oseltamivir in 15 European Countries: A Descriptive Analysis Alongside the Randomised Controlled ALICE Trial.
BACKGROUND AND OBJECTIVE
Influenza-like illness (ILI) leads to a substantial disease burden every winter in Europe; however, oseltamivir is not frequently prescribed to ILI patients in the primary-care setting. An open-label, multi-country, multi-season, randomised controlled trial investigated the effectiveness of oseltamivir for treating ILI in 15 European countries. We aimed to evaluate whether patients presenting with ILI in primary care and being managed with the addition of oseltamivir to usual care had lower average direct and indirect costs compared to patients with usual care alone.
METHODS
Resource use data were extracted from participants' daily diaries. Itemised country-specific unit costs were collected through official tariffs, pharmacies or literature. Costs were converted to 2018 values. The null hypothesis was tested based on one-sided credible intervals (CrIs) obtained by bootstrapping. Base-case analysis estimated direct cost and productivity losses using itemised costed resource use and the human capital approach. Scenario analyses with self-reported spending rather than itemised costing were also performed.
RESULTS
Patients receiving oseltamivir (N = 1306) reported fewer healthcare visits, medication uses, hospital attendances and paid-work hours lost than the other patients (N = 1298). Excluding the oseltamivir cost, the average direct costs were lower in patients treated with oseltamivir from all perspectives, but these differences were not statistically significant (perspective of patient: €17 [0-95% Crl: 16-19] vs. €24 [5-100% Crl: 18-29]; healthcare provider: €37 [28-67] vs. €44 [25-55]; healthcare payers: €54 [45-85] vs. €68 [45-81]; and society: €423 [399-478] vs. €451 [390-478]). Scenario and age-group analyses confirmed these findings, but with some between-country differences.
CONCLUSION
The average direct and indirect costs were consistently lower in patients treated with oseltamivir than in patients without from four perspectives (excluding the oseltamivir cost). However, these differences were not statistically significant.
Topics: Antiviral Agents; Cost-Benefit Analysis; Europe; Humans; Influenza, Human; Oseltamivir
PubMed: 34292510
DOI: 10.1007/s40261-021-01057-y -
AAPS PharmSciTech Mar 2020Oseltamivir is a neuraminidase inhibitor widely used to treat and prevent influenza A and B infections, although its safety and pharmacokinetics have not been evaluated...
Simulation of the Pharmacokinetics of Oseltamivir and Its Active Metabolite in Normal Populations and Patients with Hepatic Cirrhosis Using Physiologically Based Pharmacokinetic Modeling.
Oseltamivir is a neuraminidase inhibitor widely used to treat and prevent influenza A and B infections, although its safety and pharmacokinetics have not been evaluated in patients with severe hepatic impairment. A physiologically based pharmacokinetic (PBPK) model of the prodrug oseltamivir and its active metabolite, oseltamivir carboxylate (OC), was established and validated to simulate their disposition in adults and predict the exposure in patients with Child-Pugh C cirrhosis (CP-C). The simulated results from PBPK modeling and the observed data after oral administration of various oseltamivir regimens were consistent according to the fold error values of less than 2. Furthermore, the clinical observations published in the literature were comparable with our pharmacokinetic predictions. In patients with CP-C, the oseltamivir C was approximately 2-fold increased, and its AUC was approximately 6-fold higher compared with those in normal subjects. In contrast, the AUC of OC in CP-C patients did not differ significantly from that in normal subjects, whereas its C was reduced by approximately 30% in the patients. Examination of drug exposure in different health conditions indicated that the oseltamivir exposure was significantly increased in conditions with elevated cirrhosis severity, which might be associated with a higher risk of adverse drug effects, e.g., neuropsychiatric adverse events (NPAEs). In conclusion, the pharmacokinetics of oseltamivir and OC were correctly predicted by PBPK modeling. The model further predicted that the pharmacokinetics of oseltamivir might be altered in liver cirrhosis, depending on the degree of severity.
Topics: Administration, Oral; Adolescent; Adult; Aged; Antiviral Agents; Computer Simulation; Enzyme Inhibitors; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Models, Biological; Oseltamivir; Prodrugs; Young Adult
PubMed: 32128656
DOI: 10.1208/s12249-020-1638-y -
Health Technology Assessment... May 2016Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide.
OBJECTIVES
To (1) describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports (CSRs) of published and unpublished randomised, placebo-controlled trials and regulatory comments; and (2) determine the effect of oseltamivir (Tamiflu(®), Roche) treatment on mortality in patients with 2009A/H1N1 influenza.
METHODS
We searched trial registries, electronic databases and corresponded with regulators and sponsors to identify randomised trials of NIs. We requested full CSRs and accessed regulators' comments. We included only those trials for which we had CSRs. To examine the effects of oseltamivir on 2009A/H1N1 influenza mortality, we requested individual patient data (IPD) from corresponding authors of all included observational studies.
RESULTS
Effect of oseltamivir and zanamivir (Relenza®, GlaxoSmithKline) in the prevention and treatment of influenza: Oseltamivir reduced the time to first alleviation of symptoms in adults by 16.8 hours [95% confidence interval (CI) 8.4 to 25.1 hours]. Zanamivir reduced the time to first alleviation of symptoms in adults by 0.60 days (95% CI 0.39 to 0.81 days). Oseltamivir reduced unverified pneumonia in adult treatment [risk difference (RD) 1.00%, 95% CI 0.22% to 1.49%]; similar findings were observed with zanamivir prophylaxis in adults (RD 0.32%, 95% CI 0.09% to 0.41%). Oseltamivir treatment of adults increased the risk of nausea (RD 3.66%, 95% CI 0.90% to 7.39%) and vomiting (RD 4.56%, 95% CI 2.39% to 7.58%). In the treatment of children, oseltamivir induced vomiting (RD 5.34%, 95% CI 1.75% to 10.29%). Both oseltamivir and zanamivir prophylaxis reduced the risk of symptomatic influenza in individuals (oseltamivir RD 3.05%, 95% CI 1.83% to 3.88%; zanamivir RD 1.98%, 95% CI 0.98% to 2.54%) and in households (oseltamivir RD 13.6%, 95% CI 9.52% to 15.47%; zanamivir RD 14.84%, 95% CI 12.18% to 16.55%). Oseltamivir increased psychiatric adverse events in the combined on- and off-treatment periods (RD 1.06%, 95% CI 0.07% to 2.76%) and the risk of headaches while on treatment (RD 3.15%, 95% CI 0.88% to 5.78%). Effect of oseltamivir on mortality in patients with 2009A/H1N1 influenza: Analysis of summary data of 30 studies as well as IPD of four studies showed evidence of time-dependent bias. After adjusting for time-dependent bias and potential confounding variables, competing risks analysis of the IPD showed insufficient evidence that oseltamivir reduced the risk of mortality (hazard ratio 1.03, 95% CI 0.64 to 1.65).
CONCLUSIONS
Oseltamivir and zanamivir cause small reductions in the time to first alleviation of influenza symptoms in adults. The use of oseltamivir increases the risk of nausea, vomiting, psychiatric events in adults and vomiting in children. Oseltamivir has no protective effect on mortality among patients with 2009A/H1N1 influenza. Prophylaxis with either NI may reduce symptomatic influenza in individuals and in households. The balance between benefits and harms should be considered when making decisions about use of NIs for either prophylaxis or treatment of influenza.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42012002245.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Adult; Antiviral Agents; Asthma; Child; Dose-Response Relationship, Drug; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Neuraminidase; Oseltamivir; Randomized Controlled Trials as Topic; Zanamivir
PubMed: 27246259
DOI: 10.3310/hta20420 -
Pharmacoepidemiology and Drug Safety Oct 2014Influenza infection places pregnant women at greater risk of morbidity and hospitalization. The use of oseltamivir to treat influenza increased markedly in all... (Review)
Review
PURPOSE
Influenza infection places pregnant women at greater risk of morbidity and hospitalization. The use of oseltamivir to treat influenza increased markedly in all population groups during the A/H1N1pdm09 pandemic, including pregnant women. Given this increase in exposure, a reassessment of the safety of oseltamivir in pregnancy was conducted.
METHODS
The Roche Global Safety Database was searched for all exposures to oseltamivir during pregnancy in the 13 years up to 30 April 2012.
RESULTS
Of the 2926 maternal exposures to oseltamivir retrieved from the Safety Database, pregnancy outcomes were known for 2128 women. Most exposures (>90%) were reported during or after the pandemic. The incidence of adverse pregnancy outcomes in exposed women was: spontaneous abortions, 2.9% (61/2128); therapeutic abortions, 1.8% (39/2128); and pre-term deliveries, 4.2% (84 of 2000 live births), values which are lower than background rates in the general population (women with or without influenza). Fetal outcomes were known in 1875 of the 2926 exposures. For the 81 reported birth defect cases, 11 occurred during the sensitive period for the respective defects. A review of these and other case reports of birth defects did not suggest that they resulted from oseltamivir exposure.
CONCLUSIONS
The data reviewed in this article reinforce the findings of a previous review, suggesting that oseltamivir is unlikely to cause adverse pregnancy or fetal outcomes.
Topics: Antiviral Agents; Databases, Factual; Embryonic Development; Female; Fetal Development; Humans; Influenza, Human; Oseltamivir; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Product Surveillance, Postmarketing
PubMed: 24995623
DOI: 10.1002/pds.3673 -
Expert Opinion on Drug Safety Feb 2021: A potential risk of neuropsychiatric adverse events (NPAEs) of oseltamivir has remained controversial by retrospective cohort studies. This nationwide population-based...
: A potential risk of neuropsychiatric adverse events (NPAEs) of oseltamivir has remained controversial by retrospective cohort studies. This nationwide population-based cohort study aimed to assess the risk of NPAEs in influenza patients undergoing oseltamivir treatment (users) compared with a propensity score-matched cohort of patients not receiving oseltamivir (non-users). : Using the Korean National Health Service-Sample Cohort Database, patients diagnosed with incident influenza during 2003-2013 were divided into two cohorts: oseltamivir users and non-users. We calculated adjusted hazard ratios (aHRs) for the 5-day treatment course with oseltamivir using Cox regression analysis. : The incidence rate of NPAEs during 5-day oseltamivir treatment was 0.0029 and 0.0023 in oseltamivir users and non-users, respectively. The risk of NPAEs was different according to age, with an increased risk in patients aged 10-19 years (aHR 2.69, 95% CI 1.05-6.93) and a decreased risk in patients aged 0-9 years (aHR 0.46, 95% CI 0.24-0.88). The non-significant positive associations were observed in patients aged 20-64 years and those aged greater than 65 years. : Although the reason for the inverse association in children aged 0-9 years is unknown, oseltamivir could increase the risk of NPAEs for children or adolescents aged greater than 10 years.
Topics: Adolescent; Adult; Age Factors; Aged; Antiviral Agents; Child; Child, Preschool; Cohort Studies; Databases, Factual; Female; Humans; Incidence; Infant; Infant, Newborn; Influenza, Human; Male; Mental Disorders; Middle Aged; Neurotoxicity Syndromes; Oseltamivir; Republic of Korea; Retrospective Studies; Young Adult
PubMed: 33183123
DOI: 10.1080/14740338.2021.1850690 -
MSystems Oct 2023NA is a crucial surface antigen and drug target of influenza A virus. A comprehensive understanding of NA's mutational effect and drug resistance profiles is essential...
NA is a crucial surface antigen and drug target of influenza A virus. A comprehensive understanding of NA's mutational effect and drug resistance profiles is essential for comprehending the evolutionary constraints and making informed choices regarding drug selection to combat resistance in clinical settings. In the current study, we established an efficient deep mutational screening system in mouse lung tissues and systematically evaluated the fitness effect and drug resistance to three neuraminidase inhibitors of NA single-nucleotide mutations. The fitness of NA mutants is generally correlated with a natural mutation in the database. The fitness of NA mutants is influenced by biophysical factors such as protein stability, complex formation, and the immune response triggered by viral infection. In addition to confirming previously reported drug-resistant mutations, novel mutations were identified. Interestingly, we identified an allosteric drug-resistance mutation that is not located within the drug-binding pocket but potentially affects drug binding by interfering with NA tetramerization. The dual assessments performed in this study provide a more accurate assessment of the evolutionary potential of drug-resistant mutations and offer guidance for the rational selection of antiviral drugs.
Topics: Animals; Mice; Antiviral Agents; Influenza A virus; Mutation; Neuraminidase; Oseltamivir; Drug Resistance, Viral
PubMed: 37772870
DOI: 10.1128/msystems.00670-23 -
Expert Review of Clinical Pharmacology Jan 2017Over the last century several influenza outbreaks have traversed the globe, most recently the influenza A(H1N1) 2009 pandemic. On each occasion, a highly contagious,... (Review)
Review
Over the last century several influenza outbreaks have traversed the globe, most recently the influenza A(H1N1) 2009 pandemic. On each occasion, a highly contagious, virulent pathogen has emerged, leading to significant morbidity and mortality amongst those affected. Areas covered: Early antiviral therapy and supportive care is the mainstay of treatment. Treatment should be started as soon as possible and not delayed for the results of diagnostic testing. Whilst oseltamivir is still the first choice, in case of treatment failure, oseltamivir resistance should be considered, particularly in immunosuppressed patients. Here we review the antivirals currently used for management of influenza and explore a number of investigational agents that may emerge as effective antivirals including parenteral agents, combination antiviral therapy and novel agents in order to adequately target influenza virulence. Expert Commentary: New tools for rapid diagnosis and susceptible strains will help if a patient is not improving because of a resistant strain or an inadequate immune response. Further randomized control trials will be conducted to investigate the use of new antivirals and co-adjuvant therapies that will help to elucidate the process of immune modulation, particularly in immunocompetent patients.
Topics: Animals; Antiviral Agents; Disease Outbreaks; Drug Design; Drug Resistance, Viral; Drugs, Investigational; Global Health; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Oseltamivir; Severity of Illness Index
PubMed: 27797595
DOI: 10.1080/17512433.2017.1255550 -
The Journal of Antimicrobial... Nov 2017To review evidence from systematic reviews and/or meta-analyses (SR/MAs) regarding neuraminidase inhibitor (NI) safety and effectiveness. (Meta-Analysis)
Meta-Analysis Review
Safety and effectiveness of neuraminidase inhibitors for influenza treatment, prophylaxis, and outbreak control: a systematic review of systematic reviews and/or meta-analyses.
OBJECTIVES
To review evidence from systematic reviews and/or meta-analyses (SR/MAs) regarding neuraminidase inhibitor (NI) safety and effectiveness.
METHODS
We conducted an SR of SR/MAs of randomized control and/or observational studies. We searched eight electronic databases for SR/MAs that examined the effectiveness or safety of NIs administered for influenza (i.e. influenza-like illness or lab-confirmed) treatment or prophylaxis.
RESULTS
We identified 27 (0.7%) eligible SR/MAs of 3723 articles reviewed. NI (n = 2) or oseltamivir (n = 1) versus no treatment were consistently associated with a decrease in mortality odds among the hospitalized, general population (OR range 0.2 - 0.8). Oseltamivir versus no treatment was associated with a decrease in hospitalization and pneumonia risk/odds in 2/4 SR/MAs. Oseltamivir (n = 4) and zanamivir (n = 3) were consistently associated with a 0.5 - 1 day decrease in symptom duration. Oseltamivir (n = 4) or zanamivir (n = 4) versus no prophylaxis were consistently associated with a decrease in the odds/risk of symptomatic secondary transmission (OR/RR range 0.1 - 0.5). Oseltamivir versus no treatment was consistently associated with a 1.5- to 2.5-fold increase in the odds/risk of nausea (n = 4) and vomiting (n = 5).
CONCLUSIONS
NI treatment is likely to be effective at reducing mortality among hospitalized patients, and symptom duration by up to 1 day in the general population. Oseltamivir or zanamivir prophylaxis are likely to be effective at reducing secondary symptomatic influenza transmission. Increased nausea and vomiting are likely associated with oseltamivir use. We recommend that decisions regarding NI use are made in consideration of potential adverse events, particularly for the general population at low risk of complications. Among hospitalized patients, NI administration seems warranted to reduce mortality risk.
Topics: Antiviral Agents; Disease Outbreaks; Enzyme Inhibitors; Hospitalization; Humans; Influenza, Human; Neuraminidase; Oseltamivir; Pneumonia; Zanamivir
PubMed: 28961794
DOI: 10.1093/jac/dkx271