Translational Modeling of Chloroquine and Hydroxychloroquine Dosimetry in Human Airways for Treating Viral Respiratory Infections

Abstract Purpose Chloroquine and hydroxychloroquine are effective against respiratory viruses in vitro. However, they lack antiviral efficacy upon oral administration. Translation of in vitro to in vivo exposure is necessary for understanding the disconnect between the two to develop effective therapeutic strategies. Methods We employed an in vitro ion-trapping kinetic model to predict the changes in the cytosolic and lysosomal concentrations of chloroquine and hydroxychloroquine in cell lines and primary human airway cultures. A physiologically based pharmacokinetic model with detailed respiratory physiology was used to predict regional airway exposure and optimize dosing regimens. Results At their reported in vitro effective concentrations in cell lines, chloroquine and hydroxychloroquine cause a significant increase in their cytosolic and lysosomal concentrations by altering the lysosomal pH. Higher concentrations of the compounds are required to achieve similar levels of cytosolic and lysosomal changes in primary human airway cells in vitro. The predicted cellular and lysosomal concentrations in the respiratory tract for in vivo oral doses are lower than the in vitro effective levels. Pulmonary administration of aerosolized chloroquine or hydroxychloroquine is predicted to achieve high bound in vitro-effective concentrations in the respiratory tract, with low systemic exposure. Achieving effective cytosolic concentrations for activating immunomodulatory effects and adequate lysosomal levels for inhibiting viral replication could be key drivers for treating viral respiratory infections. Conclusion Our analysis provides a framework for extrapolating in vitro effective concentrations of chloroquine and hydroxychloroquine to in vivo dosing regimens for treating viral respiratory infections. Graphical abstract

A review on the effect of air pollution and exposure to PM, NO2 , O3 , SO2 , CO and heavy metals on viral respiratory infections

Journal of Air Pollution and Health ◽

10.18502/japh.v5i4.6445 ◽

2021 ◽

Author(s):

Yasaman Khajeamiri ◽

Samira Sharifi ◽

Nioosha Moradpour ◽

Alireza Khajeamiri

Keyword(s):

Heavy Metals ◽

Air Pollution ◽

Respiratory Tract ◽

Air Pollutants ◽

Respiratory Infections ◽

Ambient Air ◽

Upper Respiratory Tract ◽

Ambient Air Pollutants ◽

The ambient air pollutants that have a major role in causing respiratory diseases are particulate matter, sulfur dioxide, nitrogen dioxide, ozone, carbon monoxide, and heavy metals. In addition, respiratory infections, divided into upper respiratory tract and lower respiratory tract infection, are most commonly caused by viral agents. Thus, in light of the current COVID-19 pandemic, this review has focused on the association between exposure to general air pollution including each of the mentioned air pollutants and viral respiratory infections. The gathered evidence from the reviewed studies in this article showed that most of these air pollutants have a positive correlation with mortality, severity, transmission, inflammation, and incidence of different viral respiratory infections. Whereas, some studies found contradictory results such as non-significant and negative connections between exposure to air pollutants and viral respiratory infections, which are further discussed in this text. Therefore, following the SARS-CoV-2 outbreak, these contradictions in the reported correlation between air pollution and different aspects of viral respiratory infections must be thoroughly investigated and cleared.

Cell-Mediated Immunity in Humans During Viral Infection: Dermal Hypersensitivity and In Vitro Lymphocyte Proliferation During Mild Viral Respiratory Infections

Infection and Immunity ◽

10.1128/iai.10.4.757-761.1974 ◽

1974 ◽

Vol 10 (4) ◽

pp. 757-761 ◽

Cited By ~ 7

Author(s):

Carol A. Kauffman ◽

Calvin C. Linnemann ◽

James S. Tan ◽

Gilbert M. Schiff ◽

John P. Phair

Keyword(s):

Viral Infection ◽

Lymphocyte Proliferation ◽

Respiratory Infections ◽

Cell Mediated Immunity ◽

Severe viral respiratory infections in children with IFIH1 loss-of-function mutations

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1704259114 ◽

2017 ◽

Vol 114 (31) ◽

pp. 8342-8347 ◽

Cited By ~ 53

Author(s):

Samira Asgari ◽

Luregn J. Schlapbach ◽

Stéphanie Anchisi ◽

Christian Hammer ◽

Istvan Bartha ◽

...

Keyword(s):

Respiratory Infections ◽

In Vitro Assays ◽

Severe Illness ◽

Healthy Children ◽

Loss Of Function ◽

Life Threatening ◽

Syncytial Virus ◽

Viral respiratory infections are usually mild and self-limiting; still they exceptionally result in life-threatening infections in previously healthy children. To investigate a potential genetic cause, we recruited 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Using exome and transcriptome sequencing, we identified and characterized three rare loss-of-function variants in IFIH1, which encodes an RIG-I-like receptor involved in the sensing of viral RNA. Functional testing of the variants IFIH1 alleles demonstrated that the resulting proteins are unable to induce IFN-β, are intrinsically less stable than wild-type IFIH1, and lack ATPase activity. In vitro assays showed that IFIH1 effectively restricts replication of human respiratory syncytial virus and rhinoviruses. We conclude that IFIH1 deficiency causes a primary immunodeficiency manifested in extreme susceptibility to common respiratory RNA viruses.

Iota-carrageenan prevents the replication of SARS-CoV-2 on an in vitro respiratory epithelium model

10.1101/2021.04.27.441512 ◽

2021 ◽

Author(s):

Augusto Varese ◽

Ana Ceballos ◽

Carlos Palacios ◽

Juan Manuel Figueroa ◽

Andrea Vanesa Dugour

Keyword(s):

Sodium Chloride ◽

Antiviral Activity ◽

Nasal Spray ◽

Respiratory Infections ◽

Respiratory Epithelium ◽

Model Cell ◽

Human Use ◽

AbstractThere are, except for remdesivir, no approved antivirals for the treatment or prevention of SARS-CoV-2 infections. Iota-carrageenan formulated into a nasal spray has already been proven safe and effective in viral respiratory infections. We explored this antiviral activity in Calu-3, a human respiratory model cell line. A formula of iota-carrageenan and sodium chloride, as a nasal spray, already approved for human use, effectively inhibited SARS-CoV-2 infection in vitro, providing a more substantial reference for further clinical studies or developments.

Antiviral therapy: current concepts and practices.

Clinical Microbiology Reviews ◽

10.1128/cmr.5.2.146 ◽

1992 ◽

Vol 5 (2) ◽

pp. 146-182 ◽

Cited By ~ 51

Author(s):

B Bean

Keyword(s):

Antiviral Therapy ◽

Respiratory Infections ◽

Antiviral Agents ◽

Antiviral Drugs ◽

Virus Infections ◽

Immunodeficiency Virus ◽

Toxic Drugs ◽

Drugs capable of inhibiting viruses in vitro were described in the 1950s, but real progress was not made until the 1970s, when agents capable of inhibiting virus-specific enzymes were first identified. The last decade has seen rapid progress in both our understanding of antiviral therapy and the number of antiviral agents on the market. Amantadine and ribavirin are available for treatment of viral respiratory infections. Vidarabine, acyclovir, ganciclovir, and foscarnet are used for systemic treatment of herpesvirus infections, while ophthalmic preparations of idoxuridine, trifluorothymidine, and vidarabine are available for herpes keratitis. For treatment of human immunodeficiency virus infections, zidovudine and didanosine are used. Immunomodulators, such as interferons and colony-stimulating factors, and immunoglobulins are being used increasingly for viral illnesses. While resistance to antiviral drugs has been seen, especially among AIDS patients, it has not become widespread and is being intensely studied. Increasingly, combinations of agents are being used: to achieve synergistic inhibition of viruses, to delay or prevent resistance, and to decrease dosages of toxic drugs. New approaches, such as liposomes carrying antiviral drugs and computer-aided drug design, are exciting and promising prospects for the future.

Wheezing Associated With Respiratory Tract Infections In Children

Clinical Pediatrics ◽

10.1177/000992286600501004 ◽

1966 ◽

Vol 5 (10) ◽

pp. 586-592 ◽

Cited By ~ 6

Author(s):

Geraldine L. Freeman

Keyword(s):

Respiratory Tract ◽

Respiratory Tract Infections ◽

Respiratory Infections ◽

Tract Infections ◽

This paper reviews the known relation ships of common acute bacterial and viral respiratory infections to the asth matic state and to wheezing attacks in children. Implications for treatment are discussed in view of what has already been learned and what we need to know.

Expansion of Knowledge on OCT1 Variant Activity In Vitro and In Vivo Using Oct1/2−/− Mice

Frontiers in Pharmacology ◽

10.3389/fphar.2021.631793 ◽

2021 ◽

Vol 12 ◽

Author(s):

Bridget L. Morse ◽

Lisa Hong Chen ◽

John T. Catlow ◽

John K. Fallon ◽

Philip C. Smith ◽

...

Keyword(s):

Cell Lines ◽

Drug Exposure ◽

Systemic Exposure ◽

Organic Cation Transporter ◽

Intrinsic Activity ◽

Membrane Expression ◽

Variant Cell

The role of organic cation transporter 1 (OCT1) in humans is gaining attention as data emerges regarding its role in physiology, drug exposure, and drug response. OCT1 variants with decreased in vitro function correlate well with altered exposure of multiple OCT1 substrates in variant carriers. In the current research, we investigate mechanisms behind activity of OCT1 variants in vitro by generating cell lines expressing known OCT1 variants and quantifying membrane OCT1 protein expression with corresponding OCT1 activity and kinetics. Oct knockout mice have provided additional insight into the role of Oct1 in the liver and have reproduced effects of altered OCT1 activity observed in the clinic. To assess the complex effect of Oct1 depletion on pharmacokinetics of prodrug proguanil and its active moiety cycloguanil, both of which are OCT1 substrates, Oct1/2−/− mice were used. Decreased membrane expression of OCT1 was demonstrated for all variant cell lines, although activity was substrate-dependent, as reported previously. Lack of change in activity for OCT1*2 resulted in increased intrinsic activity per pmol of OCT1 protein, particularly for sumatriptan but also for proguanil and cycloguanil. Similar to that reported in humans with decreased OCT1 function, systemic exposure of proguanil was minimally affected in Oct1/2−/− mice. However, proguanil liver partitioning and exposure decreased. Cycloguanil exposure decreased following proguanil administration in Oct1/2−/− mice, as did the systemic metabolite:parent ratio. When administered directly, systemic exposure of cycloguanil decreased slightly; however liver partitioning and exposure were decreased in Oct1/2−/− mice. Unexpectedly, following proguanil administration, the metabolite ratio in the liver changed only minimally, and liver partitioning of cycloguanil was affected in Oct1/2−/− mice to a lesser extent following proguanil administration than direct administration of cycloguanil. In conclusion, these in vitro and in vivo data offer additional complexity in understanding mechanisms of OCT1 variant activity as well as the effects of these variants in vivo. From cell lines, it is apparent that intrinsic activity is not directly related to OCT1 membrane expression. Additionally, in situations with a more complicated role of OCT1 in drug pharmacokinetics there is difficulty translating in vivo impact simply from intrinsic activity from cellular data.

A Novel Cell-Associated Protection Assay Demonstrates the Ability of Certain Antibiotics To Protect Ocular Surface Cell Lines from Subsequent ClinicalStaphylococcus aureusChallenge

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01828-10 ◽

2011 ◽

Vol 55 (8) ◽

pp. 3788-3794 ◽

Cited By ~ 7

Author(s):

J. B. Wingard ◽

E. G. Romanowski ◽

R. P. Kowalski ◽

F. S. Mah ◽

Y. Ling ◽

...

Keyword(s):

Epithelial Cells ◽

Cell Lines ◽

Antibiotic Susceptibility ◽

Mammalian Cells ◽

Cell Layer ◽

Gentian Violet ◽

Mammalian Cell Lines ◽

Dosing Regimens

ABSTRACTIn vivoeffectiveness of topical antibiotics may depend on their ability to associate with epithelial cells to provide continued protection, but this contribution is not measured by standard antibiotic susceptibility tests. We report a newin vitromethod that measures the ability of test antibiotics azithromycin (AZM), erythromycin (ERY), tetracycline (TET), and bacitracin (BAC) to associate with mammalian cells and to protect these cells from destruction by bacteria. Mammalian cell lines were grown to confluence using antibiotic-free medium and then incubated in medium containing a single antibiotic (0 to 512 μg/ml). After incubation, the cells were challenged withStaphylococcus aureusocular isolates, without antibiotics added to the culture medium. Epithelial cell layer integrity was assessed by gentian violet staining, and the minimum cell layer protective concentration (MCPC) of an antibiotic sufficient to protect the mammalian cells fromS. aureuswas determined. Staining was also quantified and analyzed. Bacterial viability was determined by culture turbidity and growth on agar plates. Preincubation of Chang and human corneal limbal epithelial cells with AZM, ERY, and TET at ≥64 μg/ml provided protection against AZM-susceptibleS. aureusstrains, with increasing protection at higher concentrations. TET toxicity was demonstrated at >64 μg/ml, whereas AZM displayed toxicity to one cell line at 512 μg/ml. BAC failed to show consistent protection at any dose, despite bacterial susceptibility to BAC as determined by traditional antibiotic susceptibility testing. A range of antibiotic effectiveness was displayed in this cell association assay, providing data that may be considered in addition to traditional testing when determining therapeutic dosing regimens.

Place of ipratropium bromide in cough pharmacotherapy in the course of viral respiratory infections

Medycyna Faktów ◽

10.24292/01.mf.0420.9 ◽

2020 ◽

Vol 13 (4) ◽

pp. 445-448

Author(s):

Jarosław Woroń

Keyword(s):

Foreign Body ◽

Side Effects ◽

Respiratory Tract ◽

Lower Respiratory Tract ◽

Ipratropium Bromide ◽

Respiratory Infections ◽

Symptomatic Treatment ◽

A cough is an involuntary reflex or triggered by a deliberately strenuous exhalation maneuver consisting in the sudden expulsion of air from the lower respiratory tract to remove the residual secretion or a foreign body. When choosing a drug for the treatment of cough, numerous elements should be taken into account, which are intended to maximize the effectiveness of the treatment used and reduce the risk of side effects. One drug that can be used to treat symptomatic treatment of dry cough is ipratropium bromide.

For an Application of Protease Inhibitor for the Treatment of Viral Respiratory Infections - Acceptable Concentrations of a Protease Inhibitor Nafamostat and Ammonium Chloride for Direct Administration to the Respiratory Epithelium of Mice

10.21203/rs.3.rs-508075/v1 ◽

2021 ◽

Author(s):

Satoko Nakagomi

Keyword(s):

Adverse Effects ◽

Protease Inhibitor ◽

Viral Infection ◽

Viral Entry ◽

Respiratory Infections ◽

Inbred Mice ◽

Respiratory Epithelium ◽

Abstract Many enveloped respiratory viruses, including SARS-CoV-2, require host proteases for the infection, and in-vitro studies have demonstrated that protease inhibitors suppress viral infection. However, no application of inhibitors for the treatment of viral respiratory infections have been reported. This is because no method has been established to efficiently deliver inhibitors to the respiratory epithelium. This study explores methods to safely deliver a protease inhibitor nafamostat by assessing whether adverse effects occur when nafamostat is administered directly to the respiratory epithelium.To observe the effect of direct respiratory administration on organisms, inbred mice were intranasally administered the inhibitor solutions under anesthesia. 200µM nafamostat at 20µL/day for 1 week could be administered without any adverse effects. Since 1µM nafamostat is known to suppress the viral entry to cell in vitro, 200µM nafamostat is expected to show enough inhibitory effect also in mice.Ammonium chloride (NH4Cl) is also known to block the viral entry via endosome. The present study has demonstrated that 74mM NH4Cl could be also administered in the same manner. Since the NH4Cl solution at 50mM is known to efficiently suppress the entry of SARS-CoV-2 via endosome in vitro, NH4Cl may be also available to treat viral infection in vivo.Results of the present study encourage the research to apply nafamostat and also NH4Cl for the treatment of respiratory viral infection, including COVID-19.