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Journal of Fish Diseases Mar 2022Outbreaks of viral encephalopathy and retinopathy (VER) in marine and freshwater species severely devastate the aquaculture worldwide. The causative agent of VER is...
Outbreaks of viral encephalopathy and retinopathy (VER) in marine and freshwater species severely devastate the aquaculture worldwide. The causative agent of VER is nervous necrosis virus (NNV), which mainly infects the early developmental stages of fish, limiting the effectiveness of vaccines. To counter this case, the anti-NNV potentials of nine drugs with broad-spectrum antiviral activity were explored using ribavirin as a positive drug. Toxicity of the selected drugs to SSN-1 cells and grouper was firstly evaluated to determine the safety concentrations. For screening in vitro, amantadine and oseltamivir phosphate can relieve the cytopathic effects and inhibit NNV replication with the 90% inhibitory concentrations (IC ) of 38.74 and 106.75 mg/L, respectively. Amantadine has a stronger anti-NNV activity than ribavirin at the with- and post-NNV infection stages, indicating that it is a potential therapeutic agent against VER by acting directly on NNV. Similarly, amantadine also has a strong anti-NNV activity in vivo with the IC of 27.91 mg/L at the 7 days post-infection, while that was 73.25 mg/L for ribavirin. Following exposure to amantadine (40 mg/L) and ribavirin (100 mg/L) for 7 days, the survival rates of NNV-infected grouper were increased to 44% and 39%, respectively. The maximum amantadine content (11.88 mg/Kg) in grouper brain was reached following exposure for 24 hr, and amantadine can be quickly excreted from fish, reducing the risk of drug residue. Results so far indicated that amantadine is a promising therapeutic agent against NNV in aquaculture, providing an effective strategy for VER control at the early developmental stages of fish.
Topics: Amantadine; Animals; Brain Diseases; Fish Diseases; Nodaviridae; RNA Virus Infections; Retinal Diseases
PubMed: 34962648
DOI: 10.1111/jfd.13574 -
Xenobiotica; the Fate of Foreign... Feb 2022Vixotrigine is a voltage- and use-dependent sodium channel blocker under investigation for the potential treatment of neuropathic pain. One of the major metabolic...
Vixotrigine is a voltage- and use-dependent sodium channel blocker under investigation for the potential treatment of neuropathic pain. One of the major metabolic pathways of vixotrigine in humans is the hydrolysis of the carboxamide to form the carboxylic acid metabolite M14.The formation of M14 in human hepatocytes was inhibited by the carboxylesterase (CES) inhibitor Bis(4-nitrophenyl) phosphate in a concentration-dependent manner. The hydrolysis reaction was identified to be catalysed by recombinant human CES1b.Initial observation of only trace level formation of M14 in human liver microsomes at pH 7.4 caused us to doubt the involvement of CES1, an enzyme localised at the endoplasmic reticulum and the dominant carboxylesterase in human liver. Further investigation has revealed that optimal pH for the hydrolysis of vixotrigine and two other basic substrates of CES1, methylphenidate and oseltamivir, in human liver microsomes was pH 8.5-9 which is higher than their respective pK suggesting that neutral form of basic substrates is probably preferred for CES1 catalysis in liver microsomes.
Topics: Carboxylesterase; Carboxylic Ester Hydrolases; Humans; Hydrogen-Ion Concentration; Hydrolysis; Liver; Microsomes, Liver; Phenyl Ethers; Proline
PubMed: 34904522
DOI: 10.1080/00498254.2021.2018629 -
Journal of Molecular Modeling Nov 2021The synthetic cyclohexenecarboxylate ester antiviral Oseltamivir (O) have been theoretically studied by B3LYP/6-311 + + G** calculations to estimate its...
The synthetic cyclohexenecarboxylate ester antiviral Oseltamivir (O) have been theoretically studied by B3LYP/6-311 + + G** calculations to estimate its reactivity and behaviour in gas and aqueous media. The most stable structure obtained in above media is consistent with that reported experimental for Oseltamivir phosphate. The solvation energy value of (O) in aqueous media is between the predicted for antiviral Idoxuridine and Ribavirin. Besides, (O) containing a NH group and NH group reveals lower solvation energy compared with other antiviral agents with an NH group, such as Ribavirin, Cidofovir, and Brincidofovir. Atomic charges on N and O atoms in acceptors and donor groups reveal different behaviours in both media, while the natural bond orbital (NBO) studies show a raised stability of (O) in aqueous solution. This latter resulted is in concordance with the lower reactivity evidenced in water. Frontier orbital studies have revealed that (O) in gas phase has a very similar gap value to antiviral Cidofovir used against the ebola disease, while Chloroquine in the two media are more reactive than (O). This study will allow to identify (O) by using vibrational spectroscopy because the 144 vibration modes expected have been assigned using the harmonic force fields calculated from the scaled mechanical force field methodology (SQMFF). Scaled force constants for (O) in the mentioned media are also reported for first time. Due to hydration of the C = O and NH groups by solvent molecules, the calculations in solution produce variations not only in the IR wavenumbers bands, but also in their intensities.
Topics: Antiviral Agents; Density Functional Theory; Gases; Models, Chemical; Molecular Conformation; Oseltamivir; Solutions; Static Electricity; Water
PubMed: 34812947
DOI: 10.1007/s00894-021-04962-3 -
Microvascular Research Jan 2022The target of the current investigation was the delivery of oseltamivir phosphate (OSE) into the lung adenocarcinoma tissues by means of designing nanosized, non-toxic...
Oseltamivir phosphate loaded pegylated-Eudragit nanoparticles for lung cancer therapy: Characterization, prolonged release, cytotoxicity profile, apoptosis pathways and in vivo anti-angiogenic effect by using CAM assay.
The target of the current investigation was the delivery of oseltamivir phosphate (OSE) into the lung adenocarcinoma tissues by means of designing nanosized, non-toxic and biocompatible pegylated Eudragit based NPs and investigating their anticancer and antiangiogenic activity. The rationale for this strategy is to provide a novel perspective to cancer treatment with OSE loaded pegylated ERS NPs under favor of smaller particle size, biocompatible feature, cationic characteristic, examining their selective effectiveness on lung cell lines (A549 lung cancer cell line and CCD-19Lu normal cell line) and examining antiangiogenic activity by in vivo CAM analysis. For this purpose, OSE encapsulated pegylated ERS based NPs were developed and investigated for zeta potential, particle size, encapsulation efficiency, morphology, DSC, FT-IR, H NMR analyses. In vitro release, cytotoxicity, determination apoptotic pathways and in vivo CAM assay were carried out. Considering characterizations, NPs showed smaller particle size, cationic zeta potential, relatively higher EE%, nearly spherical shape, amorphous matrix formation and prolonged release pattern (Peppas-Sahlin and Weibull model with Fickian and non-Fickian release mechanisms). Flow cytometry was used to assess the apoptotic pathways using the Annexin V-FITC/PI staining assay, FITC Active Caspase-3 staining assay, and mitochondrial membrane potential detection tests. Activations on caspase-3 pathways made us think that OSE loaded pegylated ERS NPs triggered to apoptosis using intrinsic pathway. As regards to the in vivo studies, OSE loaded pegylated ERS based NPs demonstrated strong and moderate antiangiogenic activity for ERS-OSE 2 and ERS-OSE 3, respectively. With its cationic character, smaller particle size, relative superior EE%, homogenous amorphous polymeric matrix constitution indicated using solid state tests, prolonged release manner, highly selective to the human lung adenocarcinoma cell lines, could trigger apoptosis intrinsically and effectively, possess good in vivo antiangiogenic activity, ERS-OSE 2 formulation is chosen as a promising candidate and a potent drug delivery system to treat lung cancer.
Topics: A549 Cells; Acrylic Resins; Angiogenesis Inhibitors; Animals; Apoptosis; Chick Embryo; Chorioallantoic Membrane; Delayed-Action Preparations; Drug Carriers; Drug Compounding; Drug Liberation; Humans; Lung Neoplasms; Nanoparticles; Nanotechnology; Neovascularization, Pathologic; Neovascularization, Physiologic; Oseltamivir; Polyethylene Glycols
PubMed: 34520775
DOI: 10.1016/j.mvr.2021.104251 -
Nanotechnology Sep 2021Coronavirus disease 2019 (COVID-19) is today's most serious epidemic disease threatening the human race. The initial therapeutic approach of SARS-CoV-2 disease is based...
A nanotechnological approach in the current therapy of COVID-19: model drug oseltamivir-phosphate loaded PLGA nanoparticles targeted with spike protein binder peptide of SARS-CoV-2.
Coronavirus disease 2019 (COVID-19) is today's most serious epidemic disease threatening the human race. The initial therapeutic approach of SARS-CoV-2 disease is based upon the binding the receptor-binding site of the spike protein to the host cell's ACE-2 receptor on the plasma membrane. In this study, it is aimed to develop a biocompatible and biodegradable polymeric drug delivery system that is targeted to the relevant receptor binding site and provides controlled drug release. Oseltamivir phosphate (OP) is an orally administered antiviral prodrug for primary therapy of the disease in biochemically activated carboxylate form (oseltamivir carboxylate OC). In the presented study, model drug OP loaded poly(lactic--glycolic acid) (PLGA) nanoparticles (NPs) targeted with spike-binding peptide 1 (SBP1) of SARS-CoV-2 were designed to be used as an efficient and prolonged released antiviral drug delivery system. RY, EE, and DL values of the OP-loaded NPs produced by the solvent evaporation method were calculated to be 59.3%, 61.4%, and 26.9%, respectively. The particle size of OP-loaded NPs and OP-loaded NPs targeted with SBP1 peptide were 162.0 ± 11.0 and 226.9 ± 21.4 nm, respectively. While the zeta potential of the produced OP-loaded NPs was achieved negatively -23.9 ± 1.21 mV), the result of the modification with SBP1 peptide this value approached zero as -4.59 ± 0.728 mV. Morphological features of the OP-loaded NPs were evaluated using FEG-SEM. The further characterization and surface modification of the NPs were analyzed by FT-IR.release studies of NPs showed that sustained release of OP occurred for two months that fitting the Higuchi kinetic model. By evaluating these outputs, it was reported that surface modification of OP-loaded NPs was significantly effective on characteristics such as size, zeta potential values, surface functionality, and release behavior. The therapeutic model drug-loaded polymeric formulation targeted with a specific peptide may serve as an alternative to more effective and controlled release pharmaceuticals in the treatment of COVID-19 upon an extensive investigation.
Topics: Humans; Nanoparticles; Oseltamivir; Peptides; Polylactic Acid-Polyglycolic Acid Copolymer; SARS-CoV-2; Spike Glycoprotein, Coronavirus; COVID-19 Drug Treatment
PubMed: 34375967
DOI: 10.1088/1361-6528/ac1c22 -
Journal of Industrial Microbiology &... Dec 2021The aminoshikimic acid (ASA) pathway comprises a series of reactions resulting in the synthesis of 3-amino-5-hydroxybenzoic acid (AHBA), present in bacteria such as... (Review)
Review
The aminoshikimic acid (ASA) pathway comprises a series of reactions resulting in the synthesis of 3-amino-5-hydroxybenzoic acid (AHBA), present in bacteria such as Amycolatopsis mediterranei and Streptomyces. AHBA is the precursor for synthesizing the mC7N units, the characteristic structural component of ansamycins and mitomycins antibiotics, compounds with important antimicrobial and anticancer activities. Furthermore, aminoshikimic acid, another relevant intermediate of the ASA pathway, is an attractive candidate for a precursor for oseltamivir phosphate synthesis, the most potent anti-influenza neuraminidase inhibitor treatment of both seasonal and pandemic influenza. This review discusses the relevance of the key intermediate AHBA as a scaffold molecule to synthesize diverse ansamycins and mitomycins. We describe the structure and control of the expression of the model biosynthetic cluster rif in A. mediterranei to synthesize ansamycins and review several current pharmaceutical applications of these molecules. Additionally, we discuss some relevant strategies developed for overproducing these chemicals, focusing on the relevance of the ASA pathway intermediates kanosamine, AHAB, and ASA.
Topics: Actinomycetales; Anti-Bacterial Agents; Antiviral Agents; Shikimic Acid
PubMed: 34374768
DOI: 10.1093/jimb/kuab053 -
Antiviral Research Sep 2021Baloxavir marboxil (BXM) treatment-emergent polymerase acid (PA) I38X amino acid substitution (AAS) in the resistant variants of influenza viruses raise concerns...
Baloxavir marboxil (BXM) treatment-emergent polymerase acid (PA) I38X amino acid substitution (AAS) in the resistant variants of influenza viruses raise concerns regarding their emergence and spread. This study investigated the impact of 1 or 5 mg/kg BXM and 25 mg/kg oseltamivir phosphate (OS) (single or combination therapy) on the occurrence of resistance-related substitutions during the sequential lung-to-lung passages of AH1N1)pdm09 virus in mice. Deep sequencing analysis revealed that 67% (n = 4/6) of the population treated with BXM single therapy (1 or 5 mg/kg) possessed the treatment-emergent PA-I38X AAS variants (I38T, I38S, and I38V). Notably, BXM-OS combination therapy impeded PA-I38X AAS emergence. Although the doses utilized in the mouse model may not be directly translated into the clinically equivalent doses of each drugs, these findings offer insights toward alternative therapies to mitigate the emergence of influenza antiviral resistance.
Topics: Amino Acid Substitution; Animals; Antiviral Agents; Dibenzothiepins; Disease Models, Animal; Drug Resistance, Viral; Influenza A Virus, H1N1 Subtype; Mice; Morpholines; Orthomyxoviridae Infections; Oseltamivir; Pyridones; Triazines; Viral Load
PubMed: 34217753
DOI: 10.1016/j.antiviral.2021.105126 -
Journal of Cardiovascular Pharmacology May 2021Desialylation, governed by sialidases or neuraminidases, is strongly implicated in a wide range of human disorders, and accumulative data show that inhibition of...
Desialylation, governed by sialidases or neuraminidases, is strongly implicated in a wide range of human disorders, and accumulative data show that inhibition of neuraminidases, such as neuraminidases 1 sialidase, may be useful for managing atherosclerosis. Several studies have reported promising effects of oseltamivir phosphate, a widely used anti-influenza sialidase inhibitor, on human cancer cells, inflammation, and insulin resistance. In this study, we evaluated the effects of oseltamivir phosphate on atherosclerosis and thrombosis and potential liver toxicity in LDLR-/- mice fed with high-fat diet. Our results showed that oseltamivir phosphate significantly decreased plasma levels of LDL cholesterol and elastin fragmentation in aorta. However, no effect was observed on both atherosclerotic plaque size in aortic roots and chemically induced thrombosis in carotid arteries. Importantly, oseltamivir phosphate administration had adverse effects on the liver of mice and significantly increased messenger RNA expression levels of F4/80, interleukin-1β, transforming growth factor-β1, matrix metalloproteinase-12, and collagen. Taken together, our findings suggest that oseltamivir phosphate has limited benefits on atherosclerosis and carotid thrombosis and may lead to adverse side effects on the liver with increased inflammation and fibrosis.
Topics: Animals; Antiviral Agents; Aorta; Aortic Diseases; Atherosclerosis; Carotid Artery Thrombosis; Chemical and Drug Induced Liver Injury; Diet, High-Fat; Disease Models, Animal; Female; Liver; Liver Cirrhosis; Mice, Knockout; Oseltamivir; Plaque, Atherosclerotic; Receptors, LDL; Risk Assessment; Mice
PubMed: 33760798
DOI: 10.1097/FJC.0000000000001002 -
Carbohydrate Polymers May 2021Present research work was aimed at masking the bitter taste of anti- viral drug Oseltamivir phosphate (Ost) by complexing it with pea starch maltodextrin- Kleptose...
Present research work was aimed at masking the bitter taste of anti- viral drug Oseltamivir phosphate (Ost) by complexing it with pea starch maltodextrin- Kleptose Linecaps® (Mld). The Ost groups involved in triggering the bitter sensation were identified by computationally assessing its interaction with human bitter taste receptor hTAS2R 38. A series of exhaustive molecular dynamics (MD) simulation was run using Schrodinger® suite to understand the type of interaction of Ost with Mld. Experimentally, complexes of Ost with Mld were realized by solution method. The complexes were characterized using differential scanning colorimetry (DSC), fourier transform-infrared spectroscopy (FT-IR), powder X-ray diffraction (PXRD), hot stage microscopy (HSM), scanning electron microscopy (SEM), proton NMR (H-NMR) and Carbon-13 nuclear magnetic resonance (C-NMR). Ost-oral dispersible mini tablets (ODMT) were prepared by direct compression and optimised using mixture designs. Finally, bitter taste perception of Ost-ODMT was evaluated in healthy human volunteers of either sex. Computational assessment, involving interaction of Ost with bitter receptor, predicted the involvement of free amino group of Ost in triggering the bitter response whereas, MD simulation predicted the formation of stable complex between Ost and double helical confirmation of Mld. Different characterization techniques confirmed the findings of MD simulation. Results from the taste assessment in human volunteers revealed a significant reduction in bitter taste of prepared Ost-ODMT.
Topics: Aversive Agents; Drug Compounding; Female; Humans; Influenza, Human; Male; Molecular Dynamics Simulation; Oseltamivir; Polysaccharides; Solubility; Taste Perception; Young Adult
PubMed: 33712119
DOI: 10.1016/j.carbpol.2021.117703 -
Journal of Neurovirology Feb 2021As the SARS-COV-2 becomes a global pandemic, many researchers have a concern about the long COVID-19 complications. Chronic fatigue syndrome/myalgic encephalomyelitis...
As the SARS-COV-2 becomes a global pandemic, many researchers have a concern about the long COVID-19 complications. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a persistent, debilitating, and unexplained fatigue disorder. We investigated psychological morbidities such as CFS and post-traumatic stress disorder (PTSD) among survivors of COVID-19 over 6 months. All COVID-19 survivors from the university-affiliated hospital of Tehran, Iran, were assessed 6 months after infection onset by a previously validated questionnaire based on the Fukuda guidelines for CFS/EM and DSM-5 Checklist for PTSD (The Post-traumatic Stress Disorder Checklist for DSM-5 or PCL-5) to determine the presence of stress disorder and chronic fatigue problems. A total of 120 patients were enrolled. The prevalence rate of fatigue symptoms was 17.5%. Twelve (10%) screened positive for chronic idiopathic fatigue (CIF), 6 (5%) for CFS-like with insufficient fatigue syndrome (CFSWIFS), and 3 (2.5%) for CFS. The mean total scores in PCL-5 were 9.27 ± 10.76 (range:0-44), and the prevalence rate of PTSD was 5.8%. There was no significant association after adjusting between CFS and PTSD, gender, comorbidities, and chloroquine phosphate administration. The obtained data revealed the prevalence of CFS among patients with COVID-19, which is almost similar to CFS prevalence in the general population. Moreover, PTSD in patients with COVID-19 is not associated with the increased risk of CFS. Our study suggested that medical institutions should pay attention to the psychological consequences of the COVID-19 outbreak.
Topics: Adult; Aged; Antiviral Agents; COVID-19; Cough; Dementia; Drug Combinations; Dyspnea; Fatigue Syndrome, Chronic; Female; Fever; Humans; Hydroxychloroquine; Lopinavir; Male; Middle Aged; Oseltamivir; Research Design; Ritonavir; SARS-CoV-2; Severity of Illness Index; Stress Disorders, Post-Traumatic; Surveys and Questionnaires; Survivors; COVID-19 Drug Treatment
PubMed: 33528827
DOI: 10.1007/s13365-021-00949-1