scholarly journals Amantadine Inhibits SARS-CoV-2 In Vitro

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 539
Author(s):  
Klaus Fink ◽  
Andreas Nitsche ◽  
Markus Neumann ◽  
Marica Grossegesse ◽  
Karl-Heinz Eisele ◽  
...  
Keyword(s):  
Influenza A ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Topical Administration ◽  
Counter Measures ◽  
Travel Restrictions ◽  
Drug Treatments ◽  
Intranasal Instillation

Since the SARS-CoV-2 pandemic started in late 2019, the search for protective vaccines and for drug treatments has become mandatory to fight the global health emergency. Travel restrictions, social distancing, and face masks are suitable counter measures, but may not bring the pandemic under control because people will inadvertently or at a certain degree of restriction severity or duration become incompliant with the regulations. Even if vaccines are approved, the need for antiviral agents against SARS-CoV-2 will persist. However, unequivocal evidence for efficacy against SARS-CoV-2 has not been demonstrated for any of the repurposed antiviral drugs so far. Amantadine was approved as an antiviral drug against influenza A, and antiviral activity against SARS-CoV-2 has been reasoned by analogy but without data. We tested the efficacy of amantadine in vitro in Vero E6 cells infected with SARS-CoV-2. Indeed, amantadine inhibited SARS-CoV-2 replication in two separate experiments with IC50 concentrations between 83 and 119 µM. Although these IC50 concentrations are above therapeutic amantadine levels after systemic administration, topical administration by inhalation or intranasal instillation may result in sufficient amantadine concentration in the airway epithelium without high systemic exposure. However, further studies in other models are needed to prove this hypothesis.

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

scholarly journals Evaluation of mutagenicity, genotoxicity and chronic toxicity of antiviral drug imidazolyl ethanamide pentandioic acid in in vitro and in vivo test systems

2021 ◽  
Vol 98 (5) ◽  
pp. 548-557
Author(s):  
E. A. Jain ◽  
D. Pleimes ◽  
A. A. Globenko
Keyword(s):  
Oral Administration ◽  
Chromosomal Aberrations ◽  
Ames Test ◽  
Chronic Toxicity ◽  
Micronucleus Test ◽  
Human Lymphocytes ◽  
Antiviral Drug ◽  
Systemic Exposure

Introduction. The antiviral properties of imidazolyl ethanamide pentandioic acid (IPA), the active compound of the drug product, has been proven in various experimental models. However, the literature data on the toxicological properties of IPA are limited.Purpose. To evaluate mutagenic and genotoxic properties in in vitro and in vivo models, as well as to study the toxicity of IPA following chronic oral administration to rats and dogs.Materials and methods. Mutagenic and genotoxic properties of IPA were assessed using the Ames test, the test of chromosomal aberrations in human lymphocytes, and the micronucleus test in rats. The chronic toxicity of IPA was studied in Sprague Dawley rats and beagle dogs of both sexes, to which IPA was administered orally at doses of 30-300 mg/kg/day for 26 and 39 weeks, respectively.Results and discussion. In the Ames test, the addition of IPA up to the maximum dose (5000 mcg/plate) did not result in the increase in the number of revertant colonies. At a concentration of up to 5000 mcg/ml, IPA did not cause chromosomal aberrations in human leukocytes. At doses doses ≤ 2000 mg/kg, IPA did not increase the amount of micronuclei in the bone marrow of rats. In chronic experiments, animals tolerated the administration of IPA well: the dose without an observed effect (NOEL) for rats and dogs was 300 mg/kg/day.Conclusion. IPA did not show mutagenic and genotoxic properties in standard in vitro and in vivo tests. With chronic oral administration to rats and dogs, NOEL IPA equal to 300 mg/kg/day provided a systemic exposure that was 8-10 and 41-65 times higher than that in humans, respectively. The results obtained allow us to consider the safety profile of the prolonged use in humans as favorable.

scholarly journals Triple-Combination Antiviral Drug for Pandemic H1N1 Influenza Virus Infection in Critically Ill Patients on Mechanical Ventilation

2011 ◽  
Vol 55 (12) ◽  
pp. 5703-5709 ◽  
Author(s):  
Won-Young Kim ◽  
Gee Young Suh ◽  
Jin Won Huh ◽  
Sung-Han Kim ◽  
Min-ju Kim ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Critically Ill ◽  
Influenza A ◽  
Antiviral Drug ◽  
Influenza Virus Infection ◽  
Antiviral Drugs ◽  
Triple Combination ◽  
Influenza A H1n1

ABSTRACTA recentin vitrostudy showed that the three compounds of antiviral drugs with different mechanisms of action (amantadine, ribavirin, and oseltamivir) could result in synergistic antiviral activity against influenza virus. However, no clinical studies have evaluated the efficacy and safety of combination antiviral therapy in patients with severe influenza illness. A total of 245 adult patients who were critically ill with confirmed pandemic influenza A/H1N1 2009 (pH1N1) virus infection and were admitted to one of the intensive care units of 28 hospitals in Korea were reviewed. Patients who required ventilator support and received either triple-combination antiviral drug (TCAD) therapy or oseltamivir monotherapy were analyzed. A total of 127 patients were included in our analysis. Among them, 24 patients received TCAD therapy, and 103 patients received oseltamivir monotherapy. The 14-day mortality was 17% in the TCAD group and 35% in the oseltamivir group (P= 0.08), and the 90-day mortality was 46% in the TCAD group and 59% in the oseltamivir group (P= 0.23). None of the toxicities attributable to antiviral drugs occurred in either group of our study, including hemolytic anemia and hepatic toxicities related to the use of ribavirin. Logistic regression analysis indicated that the odds ratio for the association of TCAD with 90-day mortality was 0.58 (95% confidence interval, 0.24 to 1.42;P= 0.24). Although this study was retrospective and did not provide virologic outcomes, our results suggest that the treatment outcome of the triple combination of amantadine, ribavirin, and oseltamivir was comparable to that of oseltamivir monotherapy.

scholarly journals Broad-spectrum virucidal activity of bacterial secreted lipases against flaviviruses, SARS-CoV-2 and other enveloped viruses

2020 ◽  
Author(s):  
Xi Yu ◽  
Liming Zhang ◽  
Liangqin Tong ◽  
Nana Zhang ◽  
Han Wang ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Lipase Activity ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Viral Envelope ◽  
Global Public Health ◽  
Virucidal Activity ◽  
Extracellular Milieu

AbstractViruses are the major aetiological agents of acute and chronic severe human diseases that place a tremendous burden on global public health and economy; however, for most viruses, effective prophylactics and therapeutics are lacking, in particular, broad-spectrum antiviral agents. Herein, we identified 2 secreted bacterial lipases from a Chromobacterium bacterium, named Chromobacterium antiviral effector-1 (CbAE-1) and CbAE-2, with a broad-spectrum virucidal activity against dengue virus (DENV), Zika virus (ZIKV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus (HIV) and herpes simplex virus (HSV). The CbAEs potently blocked viral infection in the extracellular milieu through their lipase activity. Mechanistic studies showed that this lipase activity directly disrupted the viral envelope structure, thus inactivating infectivity. A mutation of CbAE-1 in its lipase motif fully abrogated the virucidal ability. Furthermore, CbAE-2 presented low toxicity in vivo and in vitro, highlighting its potential as a broad-spectrum antiviral drug.

scholarly journals Evaluation of Antiviral Activities of Curcumin Derivatives against HSV-1 in Vero Cell Line

2010 ◽  
Vol 5 (12) ◽  
pp. 1934578X1000501 ◽  
Author(s):  
Keivan Zandi ◽  
Elissa Ramedani ◽  
Khosro Mohammadi ◽  
Saeed Tajbakhsh ◽  
Iman Deilami ◽  
...  
Keyword(s):  
Cell Culture ◽  
Antiviral Activity ◽  
Vero Cell ◽  
Cell Line ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
In Vitro Study ◽  
Vero Cell Line ◽  
Hsv 1

Antiviral drug resistance is one of the most common problems in medicine, and, therefore, finding new antiviral agents, especially from natural resources, seems to be necessary. This study was designed to assay the antiviral activity of curcumin and its new derivatives like gallium-curcumin and Cu-curcumin on replication of HSV-1 in cell culture. The research was performed as an in vitro study in which the antiviral activity of different concentrations of three substances including curcumin, Gallium-curcumin and Cu-curcumin were tested on HSV-1. The cytotoxicity of the tested compounds was also evaluated on the Vero cell line. The CC50 values for curcumin, gallium-curcumin and Cu-curcumin were 484.2 μg/mL, 255.8 μg/mL and 326.6 μg/mL, respectively, and the respective IC50 values 33.0 μg/mL, 13.9 μg/mL and 23.1 μg/mL. The calculated SI values were 14.6, 18.4 and 14.1, respectively. The results showed that curcumin and its new derivatives have remarkable antiviral effects on HSV-1 in cell culture.

scholarly journals Ethanol Extract of Caesalpinia decapetala Inhibits Influenza Virus Infection In Vitro and In Vivo

Viruses ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 557 ◽  
Author(s):  
Li Zhang ◽  
Jungang Chen ◽  
Chang Ke ◽  
Haiwei Zhang ◽  
Shoujun Zhang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Antiviral Agents ◽  
Influenza Virus Infection ◽  
Virus Titer ◽  
Ethanol Extract ◽  
Influenza Viruses ◽  
Virus Infections

Influenza virus infections can lead to viral pneumonia and acute respiratory distress syndrome in severe cases, causing significant morbidity and mortality and posing a great threat to human health. Because of the diversity of influenza virus strains and drug resistance to the current direct antiviral agents, there have been no effective drugs as yet to cure all patients infected by influenza viruses. Natural products from plants contain compounds with diverse structures that have the potential to interact with multiple host and virus factors. In this study, we identified the ethanol extract of Caesalpinia decapetala (Roth) Alston (EEC) as an inhibitor against the replication of a panel of influenza A and B viruses both on human pulmonary epithelial A549 and human monocytic U937 cells. The animal study revealed that EEC administration reduces the weight loss and improves the survival rate of mice infected with lethal influenza virus. Also, EEC treatment attenuated lung injury and reduced virus titer significantly. In conclusion, we showed that EEC has antiviral activity both in vitro and in vivo, suggesting that the plant C. decapetala has the potential to be further developed as a resource of new anti-influenza drugs.

scholarly journals High-throughput human primary cell-based airway model for evaluating influenza, coronavirus, or other respiratory viruses in vitro

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
A. L. Gard ◽  
R. J. Luu ◽  
C. R. Miller ◽  
R. Maloney ◽  
B. P. Cain ◽  
...  
Keyword(s):  
Influenza A ◽  
Rapid Assessment ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Respiratory Viruses ◽  
Airway Epithelial Cells ◽  
Host Cells ◽  
Preclinical Model ◽  
Airway Epithelial

AbstractInfluenza and other respiratory viruses present a significant threat to public health, national security, and the world economy, and can lead to the emergence of global pandemics such as from COVID-19. A barrier to the development of effective therapeutics is the absence of a robust and predictive preclinical model, with most studies relying on a combination of in vitro screening with immortalized cell lines and low-throughput animal models. Here, we integrate human primary airway epithelial cells into a custom-engineered 96-device platform (PREDICT96-ALI) in which tissues are cultured in an array of microchannel-based culture chambers at an air–liquid interface, in a configuration compatible with high resolution in-situ imaging and real-time sensing. We apply this platform to influenza A virus and coronavirus infections, evaluating viral infection kinetics and antiviral agent dosing across multiple strains and donor populations of human primary cells. Human coronaviruses HCoV-NL63 and SARS-CoV-2 enter host cells via ACE2 and utilize the protease TMPRSS2 for spike protein priming, and we confirm their expression, demonstrate infection across a range of multiplicities of infection, and evaluate the efficacy of camostat mesylate, a known inhibitor of HCoV-NL63 infection. This new capability can be used to address a major gap in the rapid assessment of therapeutic efficacy of small molecules and antiviral agents against influenza and other respiratory viruses including coronaviruses.

scholarly journals Synthesis and antiviral activity of 4,6-bis-ethylamino[1,3,5]triazine derivatives for Flu A (H1N1) virus California/07/2009

2020 ◽  
Vol 14 (2) ◽  
Author(s):  
A. M. Demchenko ◽  
O. V. Moskalenko ◽  
V. V. Sukhoveev ◽  
O. I. Barchyna ◽  
Yu. A. Fedchenkova
Keyword(s):  
Antiviral Activity ◽  
Influenza A ◽  
H1n1 Virus ◽  
Antiviral Agents ◽  
Pharmaceutical Chemistry ◽  
Test Substance ◽  
Triazine Derivatives ◽  
Pharmacological Screening ◽  
Derivatives Of

Nowadays, control of viral diseases becomes especially relevant, considering spreading of influenza A (subtype H1N1) in this season and appearance of new coronavirus SARS-CoV-2, which caused their epidemic spreading in the world. This is why development and introduction of new highly effective antiviral drugs are a relevant direction of pharmaceutical chemistry. The aim of research is to synthesize the derivatives of (4,6-bis-amino[1,3,5]triazin-2-yl-sulphanyl)-Naryl-acetamide and to study the antiviral activity for FluA (H1N1) virus California/07/2009 at primary pharmacological screening stage. The investigated compounds – (4,6-bis-amino[1,3,5]triazin-2-yl-sulphanyl)-N-aryl-acetamide derivatives, were synthesized on the basis of 4,6-bis-ethylamino[1, 3,5]triazin-2-tiol. The antiviral activity of (4,6-bis-amino[1,3,5]triazin-2-yl-sulphanyl)-N-(2,4,6-trichlorphenyl)-acetamide against the virus FluA (H1N1) California/07/2009 was evaluated on MDCK cell culture test in vitro. It has been shown that the test substance exhibits high antiviral activity against the influenza A virus H1N1 California/ 07/2009 with effective concentration of EC50 0,6 μg/ml and the selectivity index SI > 170 (for Ribavirin SI > 160 and Amizona SI > 2,1). The data obtained substantiate the expediency of further study of derivatives of (4,6-diamino[1,3,5] triazine-2-yl-sulphanyl)-N-aryl-acetamide as potential antiviral agents.

scholarly journals Use of Cotton Rats to Evaluate the Efficacy of Antivirals in Treatment of Measles Virus Infections

2000 ◽  
Vol 44 (5) ◽  
pp. 1146-1152 ◽  
Author(s):  
Philip R. Wyde ◽  
Donna K. Moore-Poveda ◽  
Erik De Clercq ◽  
Johan Neyts ◽  
Akira Matsuda ◽  
...  
Keyword(s):  
Measles Virus ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Virus Infections ◽  
Virus Inoculation ◽  
Similar Dose ◽  
Cotton Rats ◽  
Antiviral Activities ◽  
Syncytial Virus

ABSTRACT No practical animal models for the testing of chemotherapeutic or biologic agents identified in cell culture assays as being active against measles virus (MV) are currently available. Cotton rats may serve this purpose. To evaluate this possibility, 5-ethynyl-1-β-d-ribofuranosylimidazole-4-carboxamide (EICAR) and poly(acrylamidomethyl propanesulfonate) (PAMPS), two compounds that have been reported to inhibit MV in vitro, and ribavirin, an established antiviral drug with MV-inhibitory activity, were evaluated for their antiviral activities against MV and respiratory syncytial virus (RSV) in tissue culture and in hispid cotton rats. A single administration of PAMPS markedly inhibited pulmonary RSV or MV replication (>3 log10 reduction in pulmonary titer compared to that for controls), but only if this compound was administered intranasally at about the time of virus inoculation. Both EICAR and ribavirin exhibited therapeutic activity against RSV and MV in cotton rats when they were administered parenterally. However, both of these compounds were less effective against MV. On the basis of the pulmonary virus titers on day 4 after virus inoculation, the minimal efficacious dose of EICAR against MV (120 mg/kg of body weight/day when delivered intraperitoneally twice daily) appeared to be three times lower against this virus than that of ribavirin delivered at a similar dose (i.e., 360 mg/kg/day). These findings correlated with those obtained in vitro. The data obtained suggest that cotton rats may indeed be useful for the initial evaluation of the activities of antiviral agents against MV.

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