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Journal of Biomedical Science Oct 2019Influenza is a long-standing health problem. For treatment of seasonal flu and possible pandemic infections, there is a need to develop new anti-influenza drugs that... (Review)
Review
Influenza is a long-standing health problem. For treatment of seasonal flu and possible pandemic infections, there is a need to develop new anti-influenza drugs that have good bioavailability against a broad spectrum of influenza viruses, including the resistant strains. Relenza™ (zanamivir), Tamiflu™ (the phosphate salt of oseltamivir), Inavir™ (laninamivir octanoate) and Rapivab™ (peramivir) are four anti-influenza drugs targeting the viral neuraminidases (NAs). However, some problems of these drugs should be resolved, such as oral availability, drug resistance and the induced cytokine storm. Two possible strategies have been applied to tackle these problems by devising congeners and conjugates. In this review, congeners are the related compounds having comparable chemical structures and biological functions, whereas conjugate refers to a compound having two bioactive entities joined by a covalent bond. The rational design of NA inhibitors is based on the mechanism of the enzymatic hydrolysis of the sialic acid (Neu5Ac)-terminated glycoprotein. To improve binding affinity and lipophilicity of the existing NA inhibitors, several methods are utilized, including conversion of carboxylic acid to ester prodrug, conversion of guanidine to acylguanidine, substitution of carboxylic acid with bioisostere, and modification of glycerol side chain. Alternatively, conjugating NA inhibitors with other therapeutic entity provides a synergistic anti-influenza activity; for example, to kill the existing viruses and suppress the cytokines caused by cross-species infection.
Topics: Antiviral Agents; Drug Design; Drug Development; Humans; Influenza A virus; Influenza, Human; Neuraminidase; Viral Proteins
PubMed: 31640786
DOI: 10.1186/s12929-019-0567-0 -
BMC Complementary Medicine and Therapies Feb 2023Huangqin Su (HQS) tablet is mainly composed of baicalein which has been evaluated for its ability to inhibit influenza. The present study aimed to investigate the effect...
Determination of the synergistic anti-influenza effect of Huangqin Su tablet and Oseltamivir and investigation of mechanism of the tablet based on gut microbiota and network pharmacology.
Huangqin Su (HQS) tablet is mainly composed of baicalein which has been evaluated for its ability to inhibit influenza. The present study aimed to investigate the effect of HQS and oseltamivir phosphate (OS) (single or combination therapy) on influenza-induced acute pneumonia in male and female ICR mice. The regulatory effect of HQS on gut microbiota was also studied by using 16 s rDNA sequencing, and the targets and mechanisms of HQS against influenza were comprehensively analyzed by network pharmacology. Pharmacodynamic results, including lung index and pathological changes, showed that HQS exhibited significant anti-influenza efficacy and could improve the efficacy of low-dose OS (P < 0.05 and P < 0.01, respectively). The results of 16 s rDNA sequencing revealed that HQS modulated the gut microbiota and remarkably enriched the abundance of Lactobacillus. The findings of network pharmacology research suggested that the anti-influenza mechanism of HQS was related to TLRs, MAPK, and other signal transduction pathways. Taken together, this study identified the possibility of the combined use of HQS and OS and demonstrated the role of HQS in modulating the gut microbiota of mice against influenza. Network pharmacology studies also suggested that the anti-influenza effect of HQS was related to TLRs, MAPK, TNF, and other signaling pathways.
Topics: Animals; Female; Male; Mice; DNA, Ribosomal; Gastrointestinal Microbiome; Influenza, Human; Mice, Inbred ICR; Network Pharmacology; Oseltamivir; Pneumonia; Scutellaria baicalensis
PubMed: 36739385
DOI: 10.1186/s12906-023-03858-4 -
BMC Infectious Diseases Sep 2023To study the efficacy and safety of arbidol hydrochloride tablets as a treatment for influenza-like diseases. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To study the efficacy and safety of arbidol hydrochloride tablets as a treatment for influenza-like diseases.
METHODS
In this multicenter, randomized, controlled, open label study, a total of 412 influenza-like cases were collected from 14 hospitals in seven regions of Hebei Province from September 2021 to March 2022. Patients were randomly divided into two groups. The control group (n = 207) were administered oseltamivir phosphate capsules for five days and the experimental group (n = 205) were administered arbidol hydrochloride tablets for five days. The primary endpoint was the time to normal body temperature, and the secondary endpoints included the time to remission of influenza symptoms, incidence of influenza-like complications, and incidence of adverse reactions.
RESULTS
Before treatment, there was no significant difference between the two groups in general conditions, blood routine, body temperature, or symptom severity. After treatment, there was no significant difference between the groups in the mean time to fever remission (59.24 h ± 25.21 vs. 61.05 h ± 29.47) or the mean time to remission of influenza symptoms (57.31 h ± 30.19 vs. 62.02 h ± 32.08). Survival analyses using Log-rank and Wilcoxon bilateral tests showed that there was no significant difference in fever relief time or influenza symptom relief time between the two groups. Regarding the incidence of complications and adverse events, there was only one case of tracheitis, one case of nausea, one case of vomiting, and one case of dizziness in the control group. In the experimental group, there was one case of nausea, one case of vomiting, and one case of drowsiness. In addition, one patient in the control group was hospitalized for urinary calculi.
CONCLUSION
There was no significant difference between the patients with influenza-like cases treated with arbidol hydrochloride tablets and those treated with oseltamivir phosphate capsules. Further, the patients treated with arbidol hydrochloride tablets had fewer adverse reactions, and thus, the tablets were safe to use.
Topics: Humans; Capsules; Influenza, Human; Oseltamivir; Fever; Nausea; Tablets; Phosphates
PubMed: 37674112
DOI: 10.1186/s12879-023-08570-9 -
PloS One 2015Oseltamivir phosphate is a widely used anti-influenza sialidase inhibitor. Sialylation, governed by sialyltransferases and sialidases, is strongly implicated in the...
Oseltamivir phosphate is a widely used anti-influenza sialidase inhibitor. Sialylation, governed by sialyltransferases and sialidases, is strongly implicated in the oncogenesis and progression of breast cancer. In this study we evaluated the biological behavior of canine mammary tumor cells upon oseltamivir phosphate treatment (a sialidase inhibitor) in vitro and in vivo. Our in vitro results showed that oseltamivir phosphate impairs sialidase activity leading to increased sialylation in CMA07 and CMT-U27 canine mammary cancer cells. Surprisingly, oseltamivir phosphate stimulated, CMT-U27 cell migration and invasion capacity in vitro, in a dose-dependent manner. CMT-U27 tumors xenograft of oseltamivir phosphate-treated nude mice showed increased sialylation, namely α2,6 terminal structures and SLe(x) expression. Remarkably, a trend towards increased lung metastases was observed in oseltamivir phosphate-treated nude mice. Taken together, our findings revealed that oseltamivir impairs canine mammary cancer cell sialidase activity, altering the sialylation pattern of canine mammary tumors, and leading, surprisingly, to in vitro and in vivo increased mammary tumor aggressiveness.
Topics: Animals; Antiviral Agents; Apoptosis; Blotting, Western; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Dogs; Enzyme Inhibitors; Female; Immunoenzyme Techniques; Lung Neoplasms; Mammary Neoplasms, Animal; Mice; Mice, Nude; Neoplasm Invasiveness; Neuraminidase; Oseltamivir; Tumor Cells, Cultured; Wound Healing; Xenograft Model Antitumor Assays
PubMed: 25850034
DOI: 10.1371/journal.pone.0121590 -
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 -
BMC Complementary Medicine and Therapies Jul 2023The morbidity of influenza in children increased rapidly in decade. Reduning injection (RDN), a small but fine Chinese herbal formula, has antipyretic, antiviral,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The morbidity of influenza in children increased rapidly in decade. Reduning injection (RDN), a small but fine Chinese herbal formula, has antipyretic, antiviral, anti-inflammatory effects. We intend to evaluate the efficacy and safety of RDN for the influenza in children versus Oseltamivir, explore the possible antiviral mechanism of RDN and provide evidence-based medical evidence for rational clinical drug usage.
METHOD
We design a randomized, double-blind, double-dummy, parallel control of positive drug, multi-centre clinical study. According to the formula of mean superiority test, a total of 240 patients with influenza in children will be randomized 1:1 into the experimental group and control group. The experimental group will take RDN and Oseltamivir phosphate granule simulants and the control group will take Oseltamivir phosphate granule and RDN simulants. Each group will be treated for 5 days. The primary outcome measure is temperature recovery time, and the secondary outcome measures include time when the fever begins to subside, time and degree of disease to alleviate, disappearance rate of individual symptoms and so on. We will measure before enrollment and each 24 h after treatment for comparison.
DISCUSSION
The study is launched to evaluate the efficacy and safety of RDN for the treatment of influenza in children and to provide an alternative option for influenza in children.
TRIAL REGISTRATION
This study is registered in ClinicalTrials.gov as NCT04183725, registered on 3 December, 2019.
Topics: Humans; Child; Influenza, Human; Oseltamivir; Antiviral Agents; Double-Blind Method; Phosphates
PubMed: 37474974
DOI: 10.1186/s12906-023-04037-1 -
Drug Delivery 2015This study aims to develop oseltamivir phosphate (OP) liposomes as inhalation powders by spray-drying based on the single factor investigation, which was mainly composed...
This study aims to develop oseltamivir phosphate (OP) liposomes as inhalation powders by spray-drying based on the single factor investigation, which was mainly composed of lactose, L-leucine and mannitol. It was found that the ratio of OP and liposomes (1:10), inlet temperature (110 °C) and airflow rate (2.3 mL/min) showed optimized physical properties of OP liposomes. Deposition was evaluated after the aerosolization of powders at 600 L/h via the Aerolizer® into a twin-stage impinger. The concentrations of OP and oseltamivir carboxylate (OSCA) in rats plasma using LC-MS have been determined and performed via pharmacokinetic software DAS 2.0 package. The liposomal OP dry powders displayed an average particle size around 3.5 µm with fine particle fraction (FPF = 35.40%). In vitro evaluation demonstrated a sustained release pattern accounting for 20% drug release compared to that of OP solution up to 90% drug release in 2 h. And the cumulative release percentage was up to 50% in 20 h. Atrioventricular fitting results indicated that all preparations were best fitted with a two-compartment model. There was a significant difference in MRT, Cmax and Tmax (p < 0.01) between the two groups of liposomal OP dry powders and OP solution with t-test, which indicated that the drug released slowly from liposomal OP dry powders in the lung. To sum up, dry powders formulation of liposome-encapsulated OP for inhalation was suitable for pulmonary administration, which offering the opportunity to reduce dosing frequency.
Topics: Administration, Inhalation; Animals; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Chromatography, Liquid; Dry Powder Inhalers; Lactose; Leucine; Liposomes; Mannitol; Mass Spectrometry; Oseltamivir; Particle Size; Phosphates; Powders; Rats; X-Ray Diffraction
PubMed: 24299495
DOI: 10.3109/10717544.2013.863526 -
Drug Design, Development and Therapy 2017Combination therapies against multiple targets are currently being developed to prevent resistance to a single chemotherapeutic agent and to extirpate pre-existing...
Combinatorial and sequential delivery of gemcitabine and oseltamivir phosphate from implantable poly(d,l-lactic-co-glycolic acid) cylinders disables human pancreatic cancer cell survival.
Combination therapies against multiple targets are currently being developed to prevent resistance to a single chemotherapeutic agent and to extirpate pre-existing resistance in heterogeneous cancer cells in tumors due to selective pressure from the single agent. Gemcitabine (GEM), a chemotherapeutic agent, is the current standard of care for patients with pancreatic cancer. Patients with pancreatic cancer receiving GEM have a low progression-free survival. Given the poor response rate to GEM, cancer cells are known to develop rapid resistance to this drug. Metronomic chemotherapy using combinatorial and sequential delivery systems are novel developmental approaches to disrupt tumor neovascularization, reduce systemic drug toxicity, and increase the sensitivity of chemotherapeutics in cancer. Here, implantable double-layered poly(d,l-lactic-co-glycolic acid) (PLGA) cylinders were engineered to sequentially release GEM in combination with oseltamivir phosphate (OP) over an extended time. Double-layered PLGA cylindrical implants loaded with these active hydrophilic drugs were fabricated with minimal loss of drugs during the formulation, enabling extensive control of drug loading and establishing uniform drug distribution throughout the polymer matrix. OP is used in the formulation because of its anticancer drug properties targeting mammalian neuraminidase 1 (Neu1) involved in multistage tumorigenesis. OP and GEM encapsulated in inner/outer GEM/OP or OP/GEM implantable double-layered PLGA cylinders displayed sustained near linear release over 30 days. OP and GEM released from the double-layered PLGA cylinders effectively reduced cell viability in pancreatic cancer cell line PANC1 and its GEM-resistant variant for up to 15 days.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Cell Survival; Combined Modality Therapy; Deoxycytidine; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Screening Assays, Antitumor; Humans; Lactic Acid; Molecular Structure; Oseltamivir; Pancreatic Neoplasms; Phosphorous Acids; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Structure-Activity Relationship; Gemcitabine
PubMed: 28814832
DOI: 10.2147/DDDT.S137934 -
Clinical Pharmacology and Therapeutics Feb 2024Influenza infection may lead to serious complications in the postpartum period, therefore, oseltamivir treatment in these patients and their breastfed infants is of... (Observational Study)
Observational Study
Influenza infection may lead to serious complications in the postpartum period, therefore, oseltamivir treatment in these patients and their breastfed infants is of great importance. However, the pharmacokinetics of oseltamivir in postpartum lactating women with acute influenza infection, and the consequent infant exposure to oseltamivir are still unknown, and these data would help in assessing risk and the need for dose adjustment in breastfed infants. Six lactating women with influenza-like symptoms, at a standard dose of 75 mg oral oseltamivir twice daily for 5 days, were recruited in this phase IV clinical study during the 2011/2012 H1N1 pandemic seasons. Breast milk/colostrum and venous blood samples were taken at multiple timepoints, maternal urine samples were obtained from total output within the 12-hour observational period following the seventh dose of oseltamivir. Oseltamivir phosphate (OP) reached a maximum 69.5 ± 29.4 ng/mL concentration in breast milk, higher than that found in the plasma, and showed elimination within ~ 8 hours. Oseltamivir carboxylate (active metabolite of OP) showed a lower, nearly steady-state concentration in breast milk during the observational period (maximum plasma concentration (C ) = 38.4 ± 12.9 ng/mL). Based on estimated daily milk consumption of exclusively breastfed infants, their calculated daily exposure is < 0.1% of the infant dose of oseltamivir for treatment of influenza as per marketing authorization. Here, we provide the first maternal breast milk pharmacokinetic data for oral multiple-dose oseltamivir in lactating patients with influenza and showed that its concentration in the breast milk is not sufficient to reach a therapeutic dose for breastfed infants.
Topics: Infant; Humans; Female; Oseltamivir; Influenza, Human; Antiviral Agents; Lactation; Influenza A Virus, H1N1 Subtype
PubMed: 37975276
DOI: 10.1002/cpt.3107 -
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