Oseltamivir Research Articles

Occurrence and environmental fate of anti-influenza drugs in a subcatchment of the Yodo River Basin, Japan

Understanding the current situation and risk of environmental contamination by anti-influenza drugs in aquatic environments is key to prevent the unexpected emergence and spread of drug-resistant viruses. However, few reports have been focused on newer drugs that have recently been introduced in clinical settings. In this study, the behaviour of the prodrug baloxavir marboxil (BALM)—the active ingredient of Xofluza, an increasingly popular anti-influenza drug—and its pharmacologically active metabolite baloxavir (BAL) in the aquatic environment was evaluated. Additionally, their presence in urban rivers and a wastewater treatment plant (WWTP) in the Yodo River basin was investigated and compared with those of the major anti-influenza drugs used to date (favipiravir (FAV), peramivir (PER), laninamivir (LAN), and its active metabolite, laninamivir octanoate (LANO), oseltamivir (OSE), and its active metabolite, oseltamivir carboxylate (OSEC), and zanamivir (ZAN)) to comprehensively assess their environmental fate in the aquatic environment. The results clearly showed that BALM, FAV, and BAL were rapidly degraded through photolysis (2-h, 0.6-h, and 0.4-h half-lives, respectively), followed by LAN, which was gradually biodegraded (7-h half-life). In addition, BALM and BAL decreased by up to 47 % after 4 days and 34 % after 2 days of biodegradation in river water. However, the remaining conventional drugs, except for LANO (<1 % after 10 days), were persistent, being transported from the upstream to downstream sites. The LogKd values for the rates of sorption of BALM (0.5–1.6) and BAL (1.8–3.1) on river sediment were higher than those of conventional drugs (−0.5 to 1.7). Notably, all anti-influenza drugs were effectively removed by ozonation (>90–99.9 % removal) after biological treatment at a WWTP. Thus, these findings suggest the importance of introducing ozonation to reduce pollution loads in rivers and the environmental risks associated with drug-resistant viruses in aquatic environments, thereby promoting safe river environments.

Fabrication of biocompatible water-soluble supramolecular nanofibers of oseltamivir with methyl-β-cyclodextrin for enhanced drug release

In recent times, there has been a growing interest in the advancement of nanofiber technology using materials based on cyclodextrin (CD). This heightened interest is primarily driven by their potential applications in controlled drug release. This research aims to create the nanofibers (NF) which involves incorporating an antiviral agent, oseltamivir (OTV) into the CD cavity, forming inclusion complexes (IC) that greatly improve drug encapsulation efficiency. To assess the physicochemical properties and drug-loading capabilities of these CD-based NF, a variety of characterization techniques can be utilized. It is noteworthy that NF containing OTV:MCD-IC/PVA demonstrates a continuous release of OTV (89.25%) at acidic conditions (pH 5.8) when compared to NF holding no MCD materials. Moreover, dissolution studies reveal that the resulting material is non-toxic and readily soluble in water (less than 2 min). MTT assay indicated that the examined NF are completely safe and do not have/make any adverse effects on the cells (cell viability is more than 98%). The fibroblast cells grown on nanomatrixes composed of both OTV/PVA and OTV:MCD IC/PVA NF did not display any indications of apoptosis or nuclear shrinkage. The development of such systems holds significant promise for advancing therapeutic strategies in the management of viral infections.

Comparative Effectiveness of Baloxavir Marboxil and Oseltamivir Treatment in Reducing Household Transmission of Influenza: A Post Hoc Analysis of the BLOCKSTONE Trial.

The transmission of influenza virus in households, especially by children, is a major route of infection. Prior studies suggest that timely antiviral treatment of ill cases may reduce infection in household contacts. The aim of the study was to compare the effects of oseltamivir (OTV) and baloxavir marboxil (BXM) treatment of index cases on the secondary attack rate (SAR) of influenza within household. A post hoc analysis was done in BLOCKSTONE trial-a placebo-controlled, double-blinded post-exposure prophylaxis of BXM. Data were derived from the laboratory-confirmed index cases' household contacts who received placebo in the trial and also from household members who did not participate in the trial but completed illness questionnaires. To assess the SAR of household members, multivariate analyses adjusted for factors including age, vaccination status, and household size were performed and compared between contacts of index cases treated with BXM or OTV. In total, 185 index cases (116 treated with BXM and 69 treated with OTV) and 410 household contacts (201 from trial, 209 by questionnaire) were included. The Poisson regression modeling showed that the SAR in household contacts of index cases treated with BXM and OTV was 10.8% and 18.5%, respectively; the adjusted relative reduction in SAR was 41.8% (95% confidence interval: 1.0%-65.7%, p = 0.0456) greater with BXM than OTV. Similar reductions were found in contacts from the trial and those included by questionnaire. BXM treatment of index cases appeared to result in a greater reduction in secondary household transmission than OTV treatment.

Assessment of Drug Activities against Giardia Using Hyperspectral Raman Microscopy.

This study demonstrates the capability of Raman microscopy for detecting structural differences in Giardia cells exposed to different drugs and incubation times. While metronidazole (MTZ) visibly affects the cells by inducing extracellular vesicle releases of toxic iron intermediates and modified triple-bond moieties, oseltamivir (OSM) alters the phenylalanine and lipid structures. Modifications in the heme protein environment and the transformation of iron from ferric to ferrous observed for both drug treatments are more notable for MTZ. Different contents and amounts of vesicle excretion are detected for 24 h or 48 h with MTZ incubation. At a shorter drug exposure, releases of altered proteins, glycogen, and phospholipids dominate. Agglomerates of transformed iron complexes from heme proteins and multiple-bond moieties prevail at 48 h of treatment. No such vesicle releases are present in the case of OSM usage. Drug incorporations into the cells and their impact on the plasma membrane and the dynamics of lipid raft confirmed by confocal fluorescence microscopy reveal a more destructive extent by OSM, corroborating the Raman results. Raman microscopy provides a broader understanding of the multifaceted factors and mechanisms responsible for giardiasis treatment or drug resistance by enabling a label-free, simultaneous monitoring of structural changes at the cellular and molecular levels.

Effectiveness of early pharmaceutical interventions in symptomatic COVID-19 patients: A randomized clinical trial.

We assessed the effectiveness of oral Hydroxychloroquine (HC), Azithromycin (AZ) and Oseltamivir (OS), alone or combined, among patients hospitalized with mildly symptomatic coronavirus infectious disease (COVID-19). Following the approval of the National Bioethics Committee and prospective registration (clinicaltrials.gov NCT04338698), a multicenter randomized clinical trial of adaptive design was conducted at 10 multispecialty hospitals in Pakistan. Patients were randomized into seven treatment groups. Starting April 15, 2020, consenting, eligible, otherwise healthy adult patients or those with co-morbidities under control, were recruited if they presented with mildly symptomatic COVID-19 (scored 3 on a 7-point ordinal scale anchored between 1 = not hospitalized, able to undertake normal activities, to 7 = death) confirmed by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Two primary outcomes were assessed by day seven: Turning qRT-PCR negative; and clinical improvement of two points from the baseline. Outcome rates were compared using a chi-square test. Multiple imputations were applied to handle missing data. An interim data analysis was carried out on July 19, 2020, following which the study continued without treatment group changes. Data Safety and Monitoring Board advised to stop recruitment due to its futility on January 18, 2021. Of 471 patients randomized, a total of 426 (90.4%) completed the follow-up for primary outcomes. Based on imputed data analyses at day seven: Total qRT-PCR negative cases were 137/471 (29%, 95% CI 25.0 - 33.4). By day seven, a total of 111/471 (23.5%, 95% CI 19.8 - 27.6) showed clinical improvement. No serious or non-serious adverse event was reported. Among patients with mild COVID-19, there was no statistically significant difference in the effectiveness of oral antimalarial, antiviral, or antibiotic treatments.Clinicaltrials.gov ID: NCT04338698.

Microsecond dynamics of H10N7 influenza neuraminidase reveals the plasticity of loop regions and drug resistance due to the R292K mutation.

At the beginning of the last century, multiple pandemics caused by influenza (flu) viruses severely impacted public health. Despite the development of vaccinations and antiviral medications to prevent and control impending flu outbreaks, unforeseen novel strains and continuously evolving old strains continue to represent a serious threat to human life. Therefore, the recently identified H10N7, for which not much data is available for rational structure-based drug design, needs to be further explored. Here, we investigated the structural dynamics of neuraminidase N7 upon binding of inhibitors, and the drug resistance mechanisms against the oseltamivir (OTV) and laninamivir (LNV) antivirals due to the crucial R292K mutation on the N7 using the computational microscope, molecular dynamics (MD) simulations. In this study, each system underwent long 2 × 1 μs MD simulations to answer the conformational changes and drug resistance mechanisms. These long time-scale dynamics simulations and free energy landscapes demonstrated that the mutant systems showed a high degree of conformational variation compared to their wildtype (WT) counterparts, and the LNV-bound mutant exhibited an extended 150-loop conformation. Further, the molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculation and MM/GBSA free energy decomposition were used to characterize the binding of OTV and LNV with WT, and R292K mutated N7, revealing the R292K mutation as drug-resistant, facilitated by a decline in binding interaction and a reduction in the dehydration penalty. Due to the broader binding pocket cavity of the smaller K292 mutant residue relative to the wildtype, the drug carboxylate to K292 hydrogen bonding was lost, and the area surrounding the K292 residue was more accessible to water molecules. This implies that drug resistance could be reduced by strengthening the hydrogen bond contacts between N7 inhibitors and altered N7, creating inhibitors that can form a hydrogen bond to the mutant K292, or preserving the closed cavity conformations.

In situ synthesis of multivariant zeolitic tetrazolate imidazole frameworks (ZTIFs) with uncoordinated N-heteroatom sites for efficient adsorption of antiviral drugs

The current outbreak of the coronavirus (COVID-19) pandemic has significantly increased the global usage of antiviral drugs (AVDs), leading to higher concentrations of antibiotics in water pollution. To address this current issue, a new kind of adsorbent named isostructural zeolitic tetrazolate imidazolate frameworks (ZTIFs) were synthesized by combining imidazole and tetrazolates into one self-assembly approach by adjusting pores and stability of frameworks. The incorporation of imidazole ligand progressively increased the stability of frameworks. Furthermore, increasing the content of tetrazolate ligand greatly improved the adsorption performance due to N-rich sites by increasing the pore size. The obtained adsorbent composite exhibits macroporous structure up to 53.05 nm with excellent structural stability. Owing to their macropores and highly exposed active sites, the synthesized ZTIFs exhibit the maximum adsorption capacity for oseltamivir (OT) and ritonavir (RT) of 585.2 mg/g and 435.8 mg/g, respectively. Moreover, the adsorption uptake and saturation process were rapid compared to simple MOF. Within 20 min, both pollutants achieved equilibrium. The adsorption isotherms were best interpreted by Pseudo second order kinetics. The adsorption of AVDs on ZTIFs was spontaneous, exothermic, and thermodynamically feasible. The DFT calculations and characterization results after adsorption demonstrate that π-π interaction, pore filling, surface complexation, and electrostatic interaction were the primary features of the adsorption mechanism. The prepared ZTIFs composite exhibits high chemical, mechanical and thermal stability and can be recycled multiple times without destroying its morphology and structure. The adsorbent regeneration for several cycles impacted the operational cost and the eco-friendly characteristic of the process.

COVID-19 related antiviral drugs are less adsorbable on sediment under alkaline and high cation conditions

The COVID-19 pandemic resulted in unprecedented usage and elevated environmental concentrations of antiviral drugs. However, very limited studies have reported their sorption characteristics on environmental matrices. This study investigated the sorption of six COVID-19 related antivirals on Taihu Lake sediment with varied aqueous chemistry. Results showed that the sorption isotherms for arbidol (ABD), oseltamivir (OTV), and ritonavir (RTV) were linear, while the Freundlich model was the best-fit for ribavirin (RBV) and the Langmuir model for favipiravir (FPV) and remdesivir (RDV). Their distribution coefficient, Kd, varied between 5.051 L/kg to 248.6 L/kg with the sorption capacities ranked as FPV > RDV > ABD > RTV > OTV > RBV. Alkaline conditions (pH 9) and elevated cation strength (0.05 M to 0.1 M) decreased the sorption capacities of the sediment for these drugs. Thermodynamic analysis revealed that the spontaneous sorption of RDV, ABD, and RTV was between physisorption and chemisorption while FPV, RBV, and OTV were mainly physisorption. Functional groups related to hydrogen bonds, π – π interaction, and surface complexation were implicated in the sorption processes. These findings enhance our understanding about the environmental fate of COVID-19 related antivirals and provide basic data for predicting their distribution and risk in the environment.

Factors associated with viral RNA shedding and evaluation of potential viral infectivity at returning to school in influenza outpatients after treatment with baloxavir marboxil and neuraminidase inhibitors during 2013/2014–2019/2020 seasons in Japan: an observational study

BackgroundThis study assessed the differences in daily virus reduction and the residual infectivity after the recommended home stay period in Japan in patients infected with influenza and treated with baloxavir (BA), laninamivir (LA), oseltamivir (OS), and zanamivir (ZA).MethodsWe conducted an observational study on children and adults at 13 outpatient clinics in 11 prefectures in Japan during seven influenza seasons from 2013/2014 to 2019/2020. Virus samples were collected twice from influenza rapid test-positive patients at the first and second visit 4–5 days after the start of treatment. The viral RNA shedding was quantified using quantitative RT-PCR. Neuraminidase (NA) and polymerase acidic (PA) variant viruses that reduce susceptibility to NA inhibitors and BA, respectively, were screened using RT-PCR and genetic sequencing. Daily estimated viral reduction was evaluated using univariate and multivariate analyses for the factors such as age, treatment, vaccination status, or the emergence of PA or NA variants. The potential infectivity of the viral RNA shedding at the second visit samples was determined using the Receiver Operator Curve based on the positivity of virus isolation.ResultsAmong 518 patients, 465 (80.0%) and 116 (20.0%) were infected with influenza A (189 with BA, 58 with LA, 181 with OS, 37 with ZA) and influenza B (39 with BA, 10 with LA, 52 with OS, 15 with ZA). The emergence of 21 PA variants in influenza A was detected after BA treatment, but NA variants were not detected after NAIs treatment. Multiple linear regression analysis showed that the daily viral RNA shedding reduction in patients was slower in the two NAIs (OS and LA) than in BA, influenza B infection, aged 0–5 years, or the emergence of PA variants. The residual viral RNA shedding potentially infectious was detected in approximately 10–30% of the patients aged 6–18 years after five days of onset.ConclusionsViral clearance differed by age, type of influenza, choice of treatment, and susceptibility to BA. Additionally, the recommended homestay period in Japan seemed insufficient, but reduced viral spread to some extent since most school-age patients became non-infectious after 5 days of onset.

Development of non-toxic and water-soluble nanofibers from oseltamivir in the presence of cyclodextrins for drug release

β-Cyclodextrin (BCD) and its derivative, Hydroxypropyl-β-Cyclodextrin (HCD) are cyclic oligosaccharides that present the ability to form inclusion complexes (ICs) with hydrophobic molecules and can bring new functionalities to a wide range of materials. As part of this study, water-soluble electrospun nanofibers (NFs) of oseltamivir (OTV) are tested using a variety of protocols in combination with native and its derivatives. There are some limitations to the use of oseltamivir (OTV), an antiviral drug with medium solubility in water. To improve the physical and chemical properties of OTV, β-cyclodextrin:oseltamivir inclusion complexes (OTV:BCD-ICs) and hydroxypropyl-β-cyclodextrin:oseltamivir inclusion complexes (OTV:HCD-ICs) with polyvinyl alcohol mediated nanofibers (OTV:BCD-ICs/PVA NFs, and OTV:HCD-ICs/PVA NFs) are fabricated via electrospinning. ICs are confirmed using several analytical techniques. There are a changes in the chemical shift values after the OTV molecule is introduced into the cavity of both the CDs on the surface of NFs. As shown by scanning electron microscopic images, NFs are homogeneous and particle-free. An analysis of thermogravimetric data indicated that OTV is thermostable after IC formation. Additionally, XPS analysis confirmed the presence of ICs on the surface of NFs. NFs containing OTV:BCD-ICs/PVA had a sustained release of OTV in comparison with NFs containing free material. Based on the dissolution study, the material obtained has no toxic properties and is easily water-soluble. As a result of the fabrication of NFs, OTV is released more rapidly, thus leading to the development of NFs that are non-toxic and water-soluble for creating drug delivery systems.

2189. Anti-inflammatory Activity of Lefamulin in a Mouse Model of Influenza Virus H1N1 Infection

Abstract Background Lefamulin (LEF) is a pleuromutilin antibiotic approved by the United States (US) FDA for the treatment of community-acquired bacterial pneumonia in adults. In addition to the potent antibacterial activity, LEF has demonstrated anti-inflammatory activity in an LPS induced lung neutrophilia model in mice. We investigated the anti-inflammatory activity of lefamulin in the H1N1 influenza mouse model in comparison to oseltamivir (OTV) and azithromycin (AZM). Methods Infection was performed in BALB/c mice by intranasal challenge ∼70 pfu influenza virus H1N1 A/PR/8/1934 (Day 0). Treatment with drugs at clinically relevant doses started on Day -1 (LEF 70 mg/kg/day and 110/140 mg/kg/day, s.c., AZM 30 mg/kg/day, i,p. and OTV 20 mg/kg/day p.o.) to Day 6. On Days 3 and 6, bronchioalveolar lavage fluid (BALF) was collected to measure infiltrating lung leukocytes and cytokines. Lung immunopathology following infection was evaluated on Day 6 by gross pathology at termination together with hematoxylin and eosin histopathology. Results In untreated vehicle control animals, the influenza infection progressed as expected with bodyweight loss, increased cell infiltration into the lung and increased levels of TNF-α, IL-6 at day 3 and 6. Treatment with LEF significantly decreased the total immune cell infiltration into the lung by day 6 at both doses tested (Figure Left). Cytokine levels in the BALF were significantly reduced on day 3 when the viral load peaked. Furthermore, LEF showed positive effects on lung gross pathology and survival. Oseltamivir and LEF, at both doses, appeared efficacious in the suppression of the development of influenza-induced bronchi-interstitial pneumonia, whereas azithromycin didn’t show reduced pathology (Figure Right). Anti-inflammatory effects of LEF, AZM and OTV in BALF of H1N1 infected mice infected with influenza virus H1N1. Left: Total lung leukocyte infiltrate following infection on day 0. Bars represent mean ± SEM. Right: Day 6 lung inflammation and degeneration histopathology score. Data are presented as mean histopathology score + SEM (n=10). One-way ANOVA, with Dunnett’s multiple comparisons against the vehicle control treatment was run for each timepoint. * represents significance level of p&amp;lt;0.05. ** indicates p&amp;lt;0.01. Conclusion Lefamulin showed anti-inflammatory treatment following acute influenza virus infection. Following influenza infection LEF was able to significantly reduce lung immunopathology and improve clinical outcome in mice. Results from this experiment were consistent with that observed in the LPS induced lung neutrophilia mouse model. Further studies are warranted to evaluate the immunomodulatory potential of Lefamulin. Disclosures Wolfgang W. Wicha, MSc, Nabriva Therapeutics: Grant/Research Support|Nabriva Therapeutics: Inventor|Nabriva Therapeutics: Employee|Nabriva Therapeutics: Stocks/Bonds Sandy Kimber, PhD, Nabriva Therapeutics: Grant/Research Support Charlotte Cumper, BSc, Nabriva Therapeutics: Grant/Research Support Hon S. Lam, MSc, Nabriva Therapeutics: Grant/Research Support Lorena S. Ballesteros, MSc, Nabriva Therapeutics: Grant/Research Support Christopher Kirkham, PhD, Nabriva Therapeutics: Grant/Research Support Claire Richards, PhD, Nabriva Therapeutics: Grant/Research Support Steven P. Gelone, PharmD, Nabriva Therapeutics: Board Member|Nabriva Therapeutics: Inventor|Nabriva Therapeutics: Employee|Nabriva Therapeutics: Stocks/Bonds|Nabriva Therapeutics: Stocks/Bonds Susanne Paukner, PhD, Nabriva Therapeutics: Inventor|Nabriva Therapeutics: Employee|Nabriva Therapeutics: Stocks/Bonds.

A novel and water-soluble material for coronavirus inactivation from oseltamivir in the cavity of methyl and sulfated-β-cyclodextrins through inclusion complexation

A potentially active water-soluble anti-viral with lesser toxic material from the Oseltamivir (OTV) has been produced by the sonication method. The formed material has been further characterized by UV–visible, FT-IR, powder XRD, SEM, TGA/DTA, ROESY, XPS, AFM and etc., The results of DFT calculation have proven that inclusion complexes (ICs) are theoretically and energetically more advantageous models and structures have also been proposed based on the results. Analysis of drug release has been carried out at three pH levels, and it is revealed the analysis is most helpful at acidic pH levels for the ICs with S-CD over H-CD. Over OTV without CDs, OTV:S-CD-ICs exhibited a very less cytotoxic ability on cancer cell lines than ICs with M-CD. ICs enhanced the coronavirus inactivation nature of OTV. This study provides for the first time a full characterization of ICs of OTV with CDs and highlights the impact of complexation on pharmacological activity.

Low prevalence of influenza A strains with resistance markers in Brazil during 2017-2019 seasons.

The influenza A virus (IAV) is of a major public health concern as it causes annual epidemics and has the potential to cause pandemics. At present, the neuraminidase inhibitors (NAIs) are the most widely used anti-influenza drugs, but, more recently, the drug baloxavir marboxil (BXM), a polymerase inhibitor, has also been licensed in some countries. Mutations in the viral genes that encode the antiviral targets can lead to treatment resistance. Worldwide, a low prevalence of antiviral resistant strains has been reported. Despite that, this situation can change rapidly, and resistant strain surveillance is a priority. Thus, the aim of this was to evaluate Brazilian IAVs antiviral resistance from 2017 to 2019 through the identification of viral mutations associated with reduced inhibition of the drugs and by testing the susceptibility of IAV isolates to oseltamivir (OST), the most widely used NAI drug in the country. Initially, we analyzed 282 influenza A(H1N1)pdm09 and 455 A(H3N2) genetic sequences available on GISAID. The amino acid substitution (AAS) NA:S247N was detected in one A(H1N1)pdm09 strain. We also identified NA:I222V (n = 6) and NA:N329K (n = 1) in A(H3N2) strains. In addition, we performed a molecular screening for NA:H275Y in 437 A(H1N1)pdm09 samples, by pyrosequencing, which revealed a single virus harboring this mutation. Furthermore, the determination of OST IC50 values for 222 A(H1N1)pdm09 and 83 A(H3N2) isolates revealed that all isolates presented a normal susceptibility profile to the drug. Interestingly, we detected one A(H3N2) virus presenting with PA:E119D AAS. Moreover, the majority of the IAV sequences had the M2:S31N adamantanes resistant marker. In conclusion, we show a low prevalence of Brazilian IAV strains with NAI resistance markers, in accordance with what is reported worldwide, indicating that NAIs still remain an option for the treatment of influenza infections in Brazil. However, surveillance of influenza resistance should be strengthened in the country for improving the representativeness of investigated viruses and the robustness of the analysis.

Water-soluble inclusion complexes for a novel anti-viral agent with low toxicity; Oseltamivir with the β-cyclodextrins

An innovative sonication method has been developed to produce inclusion complexes (ICs) of Oseltamivir (OTV) which is a potentially water-soluble anti-viral agent with lesser cytotoxicity. Proton signals and chemical shifts of OTV without any ambiguity confirm the formation of ICs with β-Cyclodextrin (B-CD) and Hydroxypropyl-β-cyclodextrin (H-CD). ICs are also supported by their atomic percentages as secondary evidence using XPS analysis. Analysis of drug release at three pH levels revealed the slow release of the OTV from ICs and also suitable for viral inactivation. A very less cytotoxic ability on cancer cell lines and enhanced the viral inactivation of OTV after being made into water-soluble ICs.

Fast and efficient extract oseltamivir from aquatic products using magnetic covalent organic frameworks/graphene oxide composite prior to liquid chromatography-tandem mass spectrometry analysis

In this work, a magnetic covalent organic framework/graphene oxide composite (MCOF/GO) was rapidly synthesized and developed as a promising candidate for the magnetic solid-phase extraction (MSPE). Combined with HPLC-MS, an efficient and rapid analytical method was established for the determination of oseltamivir (OS) in aquatic products. The resultant composite not only exhibited superior extraction efficiency, but also possessed fast mass transfer kinetic, reducing the pretreatment time greatly. Under optimal conditions, the linear range of the proposed method for OS determination was found to be 0.1–10 μg/kg along with a satisfactory correlation coefficient (R2 = 0.997) and a low limit of detection (LOD, 0.035 μg/kg). Furthermore, the established method was utilized to determine OS in Carp, Yellow croaker, and Shrimp, where the recoveries ranged from 87% to 116%. These results demonstrate the splendid application potential of this method to detect antiviral drugs in actual aquatic products.

Theoretical investigation of the complexation, structural, and electronic properties of complexes between oseltamivir drug and cucurbit[n = 6–9]urils

The structural geometries of cucurbit[n]uril CB[n] with n = 6–9 and their complexes with oseltamivir (OST) drug were obtained using the density functional theory computations. The stationary points of the most stable complexes were confirmed using vibrational frequency calculation. The complexation energies and electronic properties of CB[n]/OST complexes were investigated. The calculated results indicate that the intermolecular interactions in all the studied complexes occur via a large number of dipole–dipole interactions, especially hydrogen bonds between oxygen atoms of CB[n] and hydrogen atoms of amine of oseltamivir drug. The negative complexation energies of CB[n]/OST complexes in both gas and water phases indicate that the host–guest complexes are exothermic process and the complexes are more stable than its bare CB[n]. In addition, the CB[7]/OST complex is more stable than that of all studied CB[n]/OST complexes. The frequency calculation results of the most stable complexes for each of CBs indicate that complexations occur via a spontaneous process. The NBO analysis of complexes shows the transferring of partial charge from CB[n]s to oseltamivir which correspond to their MEP contours. The HOMO and the LUMO orbitals are localized on the oseltamivir in CB[n]/OST complexes. After drug complexation, the electronic properties also display that the energy gaps of CB[n] are significantly changed. All of the complexation properties point out that CB[n]s can act as a host for appropriately oseltamivir guest, even in aqueous solution.

Comparison of Intra-Familial Transmission of Influenza Virus From Index Patients Treated With Baloxavir Marboxil or Oseltamivir Using an Influenza Transmission Model and a Health Insurance Claims Database.

BackgroundInfluenza affects approximately a billion people globally, including > 10 million Japanese individuals every year. Baloxavir marboxil (baloxavir [BXM]; a selective cap-dependent endonuclease inhibitor) is approved for influenza treatment in Japan. We compared the incidence of intra-familial transmission of influenza between BXM and oseltamivir (OTV) treatments using a simulation model.MethodsUsing the JMDC Claims Database, we identified index case (IC) as the first family member diagnosed with influenza during the 2018–19 influenza season, and classified the families into BXM or OTV group per the drug dispensed to ICs. Using a novel influenza intra-familial infection model, we simulated the duration of influenza infection in ICs based on agent-specific virus shedding periods. Intra-familial infections were defined as non-IC family members infected during the agent-specific viral shedding period in ICs. The virus incubation periods in the non-IC family members were considered to exclude secondary infections from potentially external exposure. The primary endpoint was proportion of families with intra-familial infections. For between-group comparisons, we used a multivariate logistic regression model.ResultsThe median proportion of families with intra-familial transmission was 9.57% and 19.35% in the BXM (N = 84 672) and OTV (N = 62 004) groups, respectively. The multivariate odds ratio of 1.73 (2.5th–97.5th percentiles, 1.68–1.77) indicated a substantially higher incidence of intra-familial infections in the OTV group versus the BXM group. Subgroup analyses by ICs’ age category, virus type, and month of onset revealed similar trends favoring BXM.ConclusionsBXM treatment of ICs may contribute to a greater reduction in intra-familial influenza transmission than OTV treatment.

Unravelling multiple removal pathways of oseltamivir in wastewater by microalgae through experimentation and computation

Increased worldwide consumption of antiviral drugs (AVDs) amid COVID-19 has induced enormous burdens to the existing wastewater treatment systems. Microalgae-based bioremediation is a competitive alternative technology due to its simultaneous nutrient recovery and sustainable biomass production. However, knowledge about the fate, distribution, and interaction of AVDs with microalgae is yet to be determined. In this study, a concentration-determined influence of AVD oseltamivir (OT) was observed on the biochemical pathway of Chlorella sorkiniana (C.S-N1) in synthetic municipal wastewater. The results showed that high OT concentration inhibited biomass growth through increased oxidative stress and restrained photosynthesis. Nevertheless, complete OT removal was achieved at its optimized concentration of 10 mg/L by various biotic (82%) and abiotic processes (18.0%). The chemical alterations in three subtypes of extracellular polymeric substances (EPS) were primarily investigated by electrostatic (OT +8.22 mV vs. C.S-N1 −18.31 mV) and hydrophobic interactions between EPS-OT complexes supported by secondary structure protein analysis. Besides, six biodegradation-catalyzed transformation products were identified by quadrupole-time-of-flight mass spectrometer and by density functional theory. Moreover, all the TPs exhibited log Kow ≤ 5 and bioconcentration factor values of < 5000 L/kg, meeting the practical demands of environmental sustainability. This study broadens our understanding of microalgal bioadsorption and biodegradation, promoting microalgae bioremediation for nutrient recovery and AVDs removal.

Neuraminidase1 Inhibitor Protects Against Doxorubicin-Induced Cardiotoxicity via Suppressing Drp1-Dependent Mitophagy

Anthracyclines, such as doxorubicin (DOX), are among the effective chemotherapeutic drugs for various malignancies. However, their clinical use is limited by irreversible cardiotoxicity. This study sought to determine the role of neuraminidase 1 (NEU1) in DOX-induced cardiomyopathy and the potential cardio-protective effects of NEU1 inhibitor oseltamivir (OSE). Male Sprague–Dawley (SD) rats were randomized into three groups: control, DOX, and DOX + OSE. NEU1 was highly expressed in DOX-treated rat heart tissues compared with the control group, which was suppressed by OSE administration. Rats in the DOX + OSE group showed preserved cardiac function and were protected from DOX-induced cardiomyopathy. The beneficial effects of OSE were associated with the suppression of dynamin-related protein 1 (Drp1)-dependent mitochondrial fission and mitophagy. In detail, the elevated NEU1 in cardiomyocytes triggered by DOX increased the expression of Drp1, which subsequently enhanced mitochondrial fission and PINK1/Parkin pathway-mediated mitophagy, leading to a maladaptive feedback circle towards myocardial apoptosis and cell death. OSE administration selectively inhibited the increased NEU1 in myocardial cells insulted by DOX, followed by reduction of Drp1 expression, inhibition of PINK1 stabilization on mitochondria, and Parkin translocation to mitochondria, thus alleviating excessive mitochondrial fission and mitophagy, alleviating subsequent development of cellular apoptotic process. This work identified NEU1 as a crucial inducer of DOX-induced cardiomyopathy by promoting Drp1-dependent mitochondrial fission and mitophagy, and NEU1 inhibitor showed new indications of cardio-protection against DOX cardiotoxicity.

Theoretical insights into the molecular mechanism of I117V mutation in neuraminidase mediated reduction of oseltamivir drug susceptibility in A/H5N1 influenza virus

The substitution of Ile to Val at residue 117 (I117V) of neuraminidase (NA) reduces the susceptibility of the A/H5N1 influenza virus to oseltamivir (OTV). However, the molecular mechanism by which the I117V mutation affects the intermolecular interactions between NA and OTV has not been fully elucidated. In this study, we performed molecular dynamics (MD) simulations to analyze the characteristic conformational changes that contribute to the reduced binding affinity of NA to OTV after the I117V mutation. The results of MD simulations revealed that after the I117V mutation in NA, the changes in the secondary structure around the mutation site had a noticeable effect on the residue interactions in the OTV-binding site. In the case of the WT NA-OTV complex, the positively charged side chain of R118, located in the β-sheet region, frequently interacted with the negatively charged side chain of E119, which is an amino acid residue in the OTV-binding site. This can reduce the electrostatic repulsion of E119 toward D151, which is also a negatively charged residue in the OTV-binding site, so that both E119 and D151 simultaneously form hydrogen bonds with OTV more frequently, which greatly contributes to the binding affinity of NA to OTV. After the I117V mutation in NA, the side chain of R118 interacted with the side chain of E119 less frequently, likely because of the decreased tendency of R118 to form a β-sheet structure. As a result, the electrostatic repulsion of E119 toward D151 is greater than that of the WT case, making it difficult for both E119 and D151 to simultaneously form hydrogen bonds with OTV, which in turn reduces the binding affinity of NA to OTV. Hence, after the I117V mutation in NA, influenza viruses are less susceptible to OTV because of conformational changes in residues of R118, E119, and D151 around the mutation site and in the binding site.