• COVID-19 therapy: Better in combination

    From ScienceDaily@1:317/3 to All on Wed Apr 13 22:30:46 2022
    COVID-19 therapy: Better in combination than alone
    How a well-known drug can become a game changer

    Date:
    April 13, 2022
    Source:
    Charite' - Universita"tsmedizin Berlin
    Summary:
    There is a steadily growing arsenal of drugs for
    COVID-19. Researchers have studied the mechanisms of action of
    antiviral and anti-inflammatory drugs. Their findings show that
    treatment effects were best with combination therapy involving both
    types of drugs. This treatment regimen also had the additional
    benefit of increasing the time window available for antibody
    therapy.



    FULL STORY ========================================================================== There is a steadily growing arsenal of drugs for COVID-19. Researchers
    from Charite' -- Universita"tsmedizin Berlin, the Max Delbru"ck Center
    for Molecular Medicine (MDC) and Freie Universita"t (FU) Berlin have
    studied the mechanisms of action of antiviral and anti-inflammatory
    drugs. Their findings, which have been published in Molecular Therapy,show
    that treatment effects were best with combination therapy involving both
    types of drugs. This treatment regimen also had the additional benefit
    of increasing the time window available for antibody therapy.


    ========================================================================== SARS-CoV-2 infections continue to result in hospitalizations. According
    to estimates by the Robert Koch Institute, the current COVID-19
    hospitalization rate is approximately six to seven per 100,000 of the
    resident population.

    Hospitalized COVID-19 patients now have access to a range of drugs which
    can reduce the severity of the disease or, in the most severe cases,
    reduce the risk of death. Some of these drugs target the virus itself;
    others fight the inflammation associated with infection.

    First-line treatments include monoclonal antibodies and dexamethasone,
    a drug with strong anti-inflammatory properties. Antibody treatments
    neutralize the virus by sticking to the surface of its spike protein, preventing it from entering human cells. This type of treatment is used
    within seven days after symptom onset. Hospitalized COVID-19 patients who require oxygen therapy usually receive dexamethasone, a glucocorticoid
    which, for approximately 60 years, has been used to treat inflammatory conditions caused by an overactive immune response. In COVID-19, too,
    the drug has been shown to reliably dampen the body's inflammatory
    response. However, as the drug is associated with various side effects, including an increased risk of fungal infections, it should only be used
    in a specific and targeted manner.

    Researchers from Charite', the MDC's Berlin Institute of Medical Systems Biology (BIMSB) and FU Berlin have now studied the mechanisms of action
    of both types of treatment. "We uncovered evidence to suggest that
    combination therapy of antibodies and dexamethasone is more effective than either of these treatments alone," says first author Dr. Emanuel Wyler, a researcher at the BIMSB's 'RNA Biology and Posttranscriptional Regulation' research group, which is led Prof. Dr. Markus Landthaler. As not all
    lung compartments can be studied using lung tissue samples obtained from patients, the research group's first step last year was to search for
    a suitable model. That task fell to co-last author Dr. Jakob Trimpert,
    a veterinarian and research group leader at the FU Berlin's Institute
    of Virology, who subsequently developed COVID-19 hamster models. As
    animals which both contract the same virus variants as humans and develop similar disease symptoms, hamsters have proven the most important non- transgenic model for the study of COVID-19. Symptoms and progression,
    however, vary between different species of hamster. While symptoms
    usually remain moderate in Syrian hamsters, for example, Roborovski
    hamsters will develop severe disease reminiscent of that seen in COVID-19 patients requiring intensive care.

    "In the current study, we tested the effects of single and combined
    antiviral and anti-inflammatory therapies for COVID-19, meaning we
    used the existing models with monoclonal antibodies, dexamethasone,
    or a combination of the two," explains Dr. Trimpert. The FU Berlin's
    veterinary pathologists then examined infected lung tissue under a
    microscope to establish the extent of lung tissue damage. Dr. Trimpert
    and his team also determined the quantities of infectious virus and
    viral RNA present in the tissues at various time points. This enabled
    the researchers to check whether and how viral activity might change
    over the course of treatment. "Thanks to a detailed analysis of various COVID-19 parameters, which is only possible in an animal model, we were
    able to improve our understanding of the basic mechanisms of action of
    two important COVID-19 drugs. Moreover, we found clear evidence of the potential benefits associated with a combination therapy of monoclonal antibodies and dexamethasone," says Dr. Trimpert.

    Using single-cell analyses, the researchers demonstrated the drugs'
    effects on the complex interplay of various cellular signaling pathways
    and the number of immune cells present. Individual cells obtained
    from a particular sample were loaded onto a chip, where they were first barcoded and then encapsulated into minute droplets of aqueous fluid. Once prepared, the single cells underwent RNA sequencing, a process used to establish the sequence of genetic building blocks which a cell has just
    read. Thanks to barcoding, this RNA is later identifiable as originating
    from a particular cell, enabling the researchers to determine cellular
    function at the single-cell level with a high degree of accuracy. "We were
    able to observe that the antibodies are effective at reducing the amount
    of virus present," explains Dr. Wyler. He adds: "This was not much use
    in our model, though." This is because it is not the virus that damages
    the lung tissue, but the strong inflammatory response triggered by the
    virus. The immune cells fighting the invading pathogens release messenger substances to call in reinforcements. When these defensive forces arrive
    in large numbers, the lungs can become clogged. "Obstructed blood vessels
    and unstable vessel walls can subsequently result in acute lung failure," explains Dr. Wyler.

    A surprise came in the shape of the well-known drug dexamethasone. "This
    anti- inflammatory exerts a particularly strong effect on a specific kind
    of immune cell known as neutrophils," says the study's co-last author
    Dr. Geraldine Nouailles, Research Group Leader at Charite''s Department
    of Infectious Diseases and Respiratory Medicine. Neutrophils are a type
    of white blood cell responsible for mounting a prompt response to viral
    and bacterial infections.

    "The corticosteroid preparation suppresses the immune system and
    prevents the neutrophils from producing messenger substances which would attract other immune cells," explains Dr. Nouailles. She continues:
    "This makes the drug extremely effective at preventing an escalation of
    the immune response." The best treatment outcomes were achieved when the researchers administered a combination of antiviral and anti-inflammatory treatments. "This type of combination therapy is not included in existing clinical guidelines," emphasizes Dr. Nouailles. "What is more, current
    guidance stipulates that, in high-risk patients, antibody therapy can only
    be given in the first seven days following symptom onset. In clinical
    practice, dexamethasone is only used once a patient requires oxygen
    therapy, i.e., at an extremely advanced stage of the disease. Its use in combination, however, opens entirely new treatment time windows." This
    new approach must now be evaluated in clinical trials before it can be
    adopted in clinical practice.


    ========================================================================== Story Source: Materials provided by
    Charite'_-_Universita"tsmedizin_Berlin. Note: Content may be edited for
    style and length.


    ========================================================================== Journal Reference:
    1. Emanuel Wyler, Julia M. Adler, Kathrin Eschke, G. Teixeira Alves,
    Stefan
    Peidli, Fabian Pott, Julia Kazmierski, Laura Michalick, Olivia
    Kershaw, Judith Bushe, Sandro Andreotti, Peter Pennitz, Azza
    Abdelgawad, Dylan Postmus, Christine Goffinet, Jakob Kreye, S
    Momsen Reincke, Harald Pru"ss, Nils Blu"thgen, Achim D. Gruber,
    Wolfgang M. Kuebler, Martin Witzenrath, Markus Landthaler,
    Geraldine Nouailles, Jakob Trimpert. Key benefits of dexamethasone
    and antibody treatment in COVID-19 hamster models revealed
    by single-cell transcriptomics. Molecular Therapy, 2022; DOI:
    10.1016/j.ymthe.2022.03.014 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/04/220413161825.htm

    --- up 6 weeks, 2 days, 10 hours, 51 minutes
    * Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)