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Journal of Medical Virology Mar 2024Antiviral therapy based on neuraminidase (oseltamivir) or polymerase (baloxavir marboxil) inhibitors plays an important role in the management of influenza infections....
Antiviral therapy based on neuraminidase (oseltamivir) or polymerase (baloxavir marboxil) inhibitors plays an important role in the management of influenza infections. However, the emergence of drug resistance and the uncontrolled inflammatory response are major limitations in the treatment of severe influenza disease. Protectins D1 (PD1) and DX (PDX), part of a family of pro-resolving mediators, have previously demonstrated anti-influenza activity as well as anti-inflammatory properties in various clinical contexts. Herein, we synthetized a series of simplified PDX analogs and assessed their in vitro antiviral activity against influenza A(H1N1) viruses, including oseltamivir- and baloxavir-resistant variants. In ST6GalI-MDCK cells, the PDX analog AN-137B reduced viral replication in a dose-dependent manner with IC values of 23.8 for A/Puerto Rico/8/1934 (H1N1) and between 32.6 and 36.7 µM for susceptible and resistant A(H1N1)pdm09 viruses. In MTS-based cell viability experiments, AN-137B showed a 50% cellular cytotoxicity (CC ) of 638.7 µM with a resulting selectivity index of 26.8. Of greater importance, the combination of AN-137B with oseltamivir or baloxavir resulted in synergistic and additive in vitro effects, respectively. Treatment of lipopolysaccharide (LPS)-stimulated macrophages with AN-137B resulted in a decrease of iNOS activity as shown by the reduction of nitrite production, suggesting an anti-inflammatory effect. In conclusion, our results indicate that the protectin analog AN-137B constitutes an interesting therapeutic modality against influenza A virus, warranting further evaluation in animal models.
Topics: Animals; Humans; Oseltamivir; Influenza A Virus, H1N1 Subtype; Antiviral Agents; Influenza, Human; Influenza A virus; Anti-Inflammatory Agents; Drug Resistance, Viral; Neuraminidase; Triazines; Dibenzothiepins; Docosahexaenoic Acids; Morpholines; Pyridones
PubMed: 38402600
DOI: 10.1002/jmv.29484 -
Pharmaceutics Feb 2024Hepatic carboxylesterase 1 (CES1) metabolizes numerous prodrugs into active ingredients or direct-acting drugs into inactive metabolites. We aimed to develop a...
Hepatic carboxylesterase 1 (CES1) metabolizes numerous prodrugs into active ingredients or direct-acting drugs into inactive metabolites. We aimed to develop a semi-physiologically based pharmacokinetic (semi-PBPK) model to simultaneously predict the pharmacokinetics of CES1 substrates and their active metabolites in liver cirrhosis (LC) patients. Six prodrugs (enalapril, benazepril, cilazapril, temocapril, perindopril and oseltamivir) and three direct-acting drugs (flumazenil, pethidine and remimazolam) were selected. Parameters such as organ blood flows, plasma-binding protein concentrations, functional liver volume, hepatic enzymatic activity, glomerular filtration rate (GFR) and gastrointestinal transit rate were integrated into the simulation. The pharmacokinetic profiles of these drugs and their active metabolites were simulated for 1000 virtual individuals. The developed semi-PBPK model, after validation in healthy individuals, was extrapolated to LC patients. Most of the observations fell within the 5th and 95th percentiles of simulations from 1000 virtual patients. The estimated AUC and C were within 0.5-2-fold of the observed values. The sensitivity analysis showed that the decreased plasma exposure of active metabolites due to the decreased CES1 was partly attenuated by the decreased GFR. Conclusion: The developed PBPK model successfully predicted the pharmacokinetics of CES1 substrates and their metabolites in healthy individuals and LC patients, facilitating tailored dosing of CES1 substrates in LC patients.
PubMed: 38399287
DOI: 10.3390/pharmaceutics16020234 -
Science Advances Feb 2024Seasonal 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...
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.
Topics: Animals; Mice; Oseltamivir; Influenza A virus; Antiviral Agents; Oxazines; Pyridines; Thiepins; Dibenzothiepins; Morpholines; Pyridones; Triazines
PubMed: 38394202
DOI: 10.1126/sciadv.adk9004 -
Haematologica Jun 2024
Topics: Humans; Oseltamivir; Male; Female; Antiviral Agents; Platelet Count; Hospitalization; Blood Platelets; Databases, Factual; Middle Aged; Aged; Adult; Influenza, Human; COVID-19 Drug Treatment
PubMed: 38385256
DOI: 10.3324/haematol.2023.283731 -
Current Medicinal Chemistry Feb 2024Influenza is an acute respiratory disease caused by influenza viruses. It has the characteristics of fast transmission and strong infectivity, and it does great harm to...
Influenza is an acute respiratory disease caused by influenza viruses. It has the characteristics of fast transmission and strong infectivity, and it does great harm to human health and survival. It is estimated that the seasonal influenza epidemics every year will cause about one billion cases of infections and hundreds of thousands of deaths worldwide, while influenza A virus is the leading cause of infection and death. Currently, the main drugs used in clinics to treat influenza viruses are neuraminidase inhibitors, and these drugs have shown excellent efficacy in treating influenza viruses. However, various mutant strains have developed resistance to these effective drugs in clinics (such as the subtype mutant strains of H274Y in H1N1 or H5N1 and E119V in H3N2 have developed resistance to Oseltamivir). Influenza viruses mutate frequently, and new viral strains are constantly discovered, and the pandemics will break out at any time. Therefore, it is urgent to develop efficient and broad-spectrum drugs to prevent and treat the influenza pandemic caused by the emerging new subtypes. This review focuses on describing the pandemic history, the structure, function and prevention methods of influenza viruses and the progress of the development of anti-influenza drugs, to provide the reference for prevention and treatment of influenza viruses and development of influenza virus inhibitors.
PubMed: 38362681
DOI: 10.2174/0109298673268314231204061224 -
International Journal of Antimicrobial... Apr 2024Oseltamivir is a low-cost antiviral agent that could support or complement treatment of COVID-19. This study assessed whether oseltamivir is effective in reducing...
BACKGROUND
Oseltamivir is a low-cost antiviral agent that could support or complement treatment of COVID-19. This study assessed whether oseltamivir is effective in reducing COVID-19-related mortality.
METHODS
This retrospective cohort study evaluated real-world data from a nationwide database of hospitalisation due to severe acute respiratory syndrome in Brazil. Propensity score matching was used to mimic a randomised controlled trial with 'oseltamivir' and 'no antivirals at all' as the intervention and control groups, respectively.
RESULTS
A total of 21 480 and 268 486 patients admitted between February 2020 and January 2023 were included in the intervention and control groups, respectively. After matching, the odds ratio (OR) for death was 0.901 (95% confidence interval [CI] 0.873-0.930). The OR (95% CI) for death in patients who were admitted to the ICU, and on non-invasive or invasive ventilation was 0.868 (0.821-0.917), 0.935 (0.893-0.980), and 0.883 (0.814-0.958), respectively.
CONCLUSIONS
Overall, the use of oseltamivir was associated with an attributable risk reduction of 2.50% (95% CI 1.77-3.29). Similar results were observed in patients who were admitted to the ICU, and on non-invasive or invasive ventilation. Oseltamivir is a low-cost potential antiviral treatment for COVID-19.
Topics: Humans; Antiviral Agents; COVID-19; Hospital Mortality; Oseltamivir; Retrospective Studies; Randomized Controlled Trials as Topic
PubMed: 38354825
DOI: 10.1016/j.ijantimicag.2024.107111 -
Cureus Jan 2024Background The COVID-19 pandemic has posed an unprecedented challenge to the global healthcare system, necessitating effective therapeutic strategies to mitigate its...
Background The COVID-19 pandemic has posed an unprecedented challenge to the global healthcare system, necessitating effective therapeutic strategies to mitigate its impact. This study investigates the significance of early antiviral therapy in the context of intensive care units (ICUs) and its potential to influence the progression and outcomes of severe COVID-19 cases. Methodology This retrospective cohort study leveraged a diverse patient population with confirmed severe COVID-19 admitted to ICUs. A total of 1,250 patients were included in the analysis, and their medical records were comprehensively reviewed. The study aimed to assess the impact of early antiviral therapy on patient outcomes, focusing on the administration of remdesivir within the first 48 hours of ICU admission. Results In a study of 1,250 COVID-19 patients, early antiviral therapy with remdesivir significantly reduced ICU admissions by 30% (N = 225) compared to standard care (N = 525). The early therapy group also exhibited a 20% lower mortality rate (N = 120) than the control group (N = 150). Demographic associations with antiviral usage were observed. Kaletra was favored by females, non-Saudi individuals, and healthcare workers, while favipiravir was associated with gender. Remdesivir and ribavirin use were linked to gender and Saudi nationality, while oseltamivir was related to gender, Saudi nationality, and body mass index. Microbiological cure rates were 15.4%, with 84.6% not achieving it. ICU outcomes included 37.7% deaths, 55.7% home discharges, and 6.6% transfers, while hospital outcomes featured 38.5% deaths, 54.4% home discharges, and 7.1% transfers. Conclusions This study presents a comprehensive analysis of COVID-19 patient demographics, antiviral medication associations, and clinical outcomes. The findings highlight the significance of tailoring treatment strategies based on patient characteristics and viral history. These insights contribute to a deeper understanding of COVID-19 management and can inform clinical decision-making and further research in this field.
PubMed: 38344559
DOI: 10.7759/cureus.52096 -
Transplant Infectious Disease : An... Apr 2024Neuraminidase inhibitors, including oseltamivir, are the treatment standard for influenza. Baloxavir, a novel antiviral, demonstrated comparable outcomes to oseltamivir...
BACKGROUND
Neuraminidase inhibitors, including oseltamivir, are the treatment standard for influenza. Baloxavir, a novel antiviral, demonstrated comparable outcomes to oseltamivir in outpatients with influenza. Baloxavir was equally effective as oseltamivir in a retrospective study of hospitalized patients with influenza at our institution. However, the efficacy of baloxavir in immunocompromised patients is unclear.
METHODS
We conducted a retrospective cohort study of immunocompromised adult patients hospitalized with influenza A who received baloxavir from January 2019 to April 2019 or oseltamivir from January 2018 to April 2018. Demographic and clinical outcomes were assessed. Primary outcomes were time from antiviral initiation to resolution of hypoxia and fever. Secondary outcomes were length of stay (LOS), intensive care unit (ICU) care, ICU LOS, and 30-day mortality.
RESULTS
Of 95 total patients, 52 received baloxavir and 43 received oseltamivir. Other than younger age (57.5 vs. 65; p = .035) and longer duration between vaccination and symptom onset (114 vs. 86 days; p = .001) in the baloxavir group, baseline characteristics did not differ. H1 was the predominant subtype in the baloxavir group (65.3%) versus H3 in the oseltamivir group (85.7%). When comparing baloxavir to oseltamivir, there was no significant difference in median time from antiviral initiation to resolution of hypoxia (59.9 vs. 42.5 h) and to resolution of fever (21.6 vs. 26.6 h). There were no differences in secondary outcomes.
CONCLUSION
Baloxavir was not associated with longer time to resolution of hypoxia or fever in comparison to oseltamivir. Results must be taken in context of variations in seasonal influenza subtype and resistance rates.
Topics: Adult; Humans; Oseltamivir; Influenza, Human; Retrospective Studies; Oxazines; Pyridines; Thiepins; Antiviral Agents; Immunocompromised Host; Hypoxia; Dibenzothiepins; Morpholines; Pyridones; Triazines
PubMed: 38319665
DOI: 10.1111/tid.14249 -
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