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Friday, April 2, 2021

Study identifies possible COVID-19 drugs including several FDA-approved

 A team led by scientists in the Perelman School of Medicine at the University of Pennsylvania has identified nine potential new COVID-19 treatments, including three that are already approved by the Food and Drug Administration (FDA) for treating other diseases.

The team, whose findings were published in Cell Reports, screened thousands of existing drugs and drug-like molecules for their ability to inhibit the replication of the COVID-19-causing coronavirus, SARS-CoV-2. In contrast to many prior studies, the screens tested the molecules for anti-coronaviral activity in a variety of cell types, including human airway-lining cells that are similar to the ones principally affected in COVID-19.

Of the nine drugs found to reduce SARS-CoV-2 replication in respiratory cells, three already have FDA approval: the transplant-rejection drug cyclosporine, the cancer drug dacomitinib, and the antibiotic salinomycin. These could be rapidly tested in human volunteers and COVID-19 patients.

The experiments also shed light on key processes the coronavirus uses to infect different cells and found that the antiviral drug remdesivir, which has an FDA Emergency Use Authorization for treating COVID-19, does appear to work against the virus in cell-culture tests on respiratory cells, whereas hydroxychloroquine does not.

"Our discoveries here suggest new avenues for therapeutic interventions against COVID-19, and also underscore the importance of testing candidate drugs in respiratory cells," said co-senior author Sara Cherry, PhD, a professor of Pathology and Laboratory Medicine and scientific director of the High-Throughput Screening (HTS) Core at Penn Medicine.

Study collaborators included co-senior authors David Schultz, PhD, technical director of the HTS Core, and Holly Ramage, PhD, assistant professor of microbiology & immunology at Thomas Jefferson University.

Although great progress has been made in the development of vaccines and treatments for the SARS-CoV-2 coronavirus, there is still much room for improvement. In the United States, the only antiviral COVID-19 treatments that have received FDA Emergency Use Authorization -- remdesivir and several anti-SARS-CoV-2 antibody preparations -- are expensive and far from 100 percent effective.

For their screening project, Cherry and colleagues assembled a library of 3,059 compounds, including about 1,000 FDA-approved drugs and more than 2,000 drug-like molecules that have shown activity against defined biological targets. They then tested all of these for their ability to significantly inhibit SARS-CoV-2 replication in infected cells, without causing much toxicity.

Initially, they performed antiviral screens using cell types they could grow easily in the lab and infect with SARS-CoV-2, namely African Green Monkey kidney cells, and a cell line derived from human liver cells. With these screens, they identified and validated several compounds that worked in the monkey kidney cells, and 23 that worked in the human liver cells. Hydroxychloroquine, which is used as a malaria drug, and remdesivir, were effective in both cell types.

Since SARS-CoV-2 is mainly a respiratory virus and is thought to initiate infections via airway-lining cells, the researchers sought a respiratory cell type that they could infect experimentally with the virus. They eventually identified a suitable cell line, Calu-3, that is derived from human airway-lining cells. They used these respiratory-derived cells to test the antiviral compounds identified through the human liver cell screen, and found that only nine had activity in the new cells. The nine did not include hydroxychloroquine. (Remdesivir worked in the Calu-3 cells but was not included in the list because it is already in use against COVID-19.)

By identifying different sets of drugs that work in different cell types, the researchers also shed light on the mechanisms SARS-CoV-2 uses to gain entry to cells. The findings suggest that in kidney and liver cells, the virus uses a mechanism that can be disrupted, for example, by hydroxychloroquine; yet the virus appears to use a different mechanism in respiratory cells, thus explaining hydroxychloroquine's lack of success in those cells -- and in COVID-19 clinical trials.

The nine antivirals active in respiratory cells did include salinomycin, a veterinary antibiotic that is also being investigated as an anticancer drug; the kinase enzyme inhibitor dacomitinib, an anticancer drug; bemcentinib, another kinase inhibitor now being tested against cancers; the antihistamine drug ebastine; and cyclosporine, an immune suppressing drug commonly used to prevent the immune rejection of transplanted organs.

The study highlights cyclosporine as particularly promising, as it appears to works against SARS-CoV-2 in respiratory and non-respiratory cells, and via two distinct mechanisms: inhibiting cell enzymes called cyclophilins, which the coronavirus hijacks to support itself, and suppressing the potentially lethal inflammation of severe COVID-19.

"There may be important benefits to the use of cyclosporine in hospitalized COVID-19 patients, and ongoing clinical trials at Penn and elsewhere are testing that hypothesis," Cherry said.

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The research was supported by funding from the National Institutes of Health (5R01AI140539, 1R01AI1502461, R01AI152362), the Mark Foundation, the Dean's Innovation Fund, the Laddie and Linda Montague Foundation, the Burroughs Wellcome Fund, Mercatus, and the Bill and Melinda Gates Foundation.

https://www.eurekalert.org/pub_releases/2021-04/uops-sip040221.php

Health professionals with dependents at high risk of quitting after COVID-19

 Up to one in five employees at an academic medical institution are considering leaving their professions due to the strains of coping with the pandemic in their own lives, according to a new University of Utah Health study. Individuals who had caregiving responsibilities were among those most likely to contemplate leaving or reducing hours.

The findings suggest that retaining highly trained doctors, nurses, and scientists in the aftermath of the COVID-19 pandemic could be the next great health care challenge.

"It's sobering to learn that, during a time of economic recession, at least one-fifth of our workforce were considering leaving their jobs because of the severe levels of stress they were experiencing," says Angela Fagerlin, Ph.D., the study's senior author and professor and chair of the Department of Population Health Sciences at the University of Utah School of Medicine. "Many of these are people who have spent five to ten years of their adult lives training to do this kind of work. Yet, it's so overwhelming and burdensome that they were potentially thinking about giving it all up."

Although conducted at a single health care system, the researchers say these findings could have broader implications.

"We suspect these disturbing trends likely exist within other health care systems nationwide," says Rebecca Delaney, Ph.D., the study's lead author and a postdoctoral research fellow at the U of U School of Medicine. "These findings are alarming and a warning sign about the morale and well-being of doctors and nurses, as well as non-clinical health care scientists and staff."

The study appears in JAMA Network Open.

Several studies have examined the effects of burnout, stress, depression, and anxiety on frontline medical staff during the global pandemic. However, most have only included frontline workers or physician trainees. Few of these studies have addressed important family-work balance issues, such as childcare needs during the pandemic, which contribute significantly to the stress and burnout of staff.

To remedy this oversight, Delaney and her colleagues distributed a web-based survey of all 27,700 clinical and non-clinical U of U Health faculty, staff, and trainees in August 2020. Survey items measured childcare needs, work-life balance needs, career development impact, and stress related to the pandemic.

Overall, 18 percent (n=5,030) completed the entire survey. The data was consistent across clinical and non-clinical respondents, confirming that everyone--men, women, those with and without children--were struggling with the impact of COVID-19, Delaney says.

Nearly half (48 percent) reported having at least one child 18 years old or younger. In addition, the researchers found:

  • 49 percent of those who had children reported that parenting and managing virtual education for children was causing them stress
  • Faculty (55 percent) and trainees (60 percent) reported decreased productivity
  • 47 percent of participants expressed concern about COVID-19 affecting their career development, with 64 percent of trainees being highly concerned
  • 30 percent reported considering reducing hours
  • 21 percent reported considering leaving the workforce

In addition to being a single health care system survey, other study limitations included the possibility of selection bias among those who chose to complete the survey. It's also possible that more employees with children aged 18 or younger responded than those without children.

Although the researchers found that burnout, depression, and anxiety were important, they concluded that greater emphasis on work-life balance, accessibility to dependent care, and ongoing psychological and social support could prevent thousands of medical caregivers from joining this potentially devastating exodus.

"Health care systems must develop effective ways to ensure that well-trained clinicians, support staff, and non-clinical scientists are supported during this unprecedented time as well as after it," Fagerlin says. "If they do that, then health systems will be more likely to retain a diverse and effective workforce."

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In addition to Drs. Delaney and Fagerlin, U of U Health scientists Amy Locke, Mandy L. Pershing, Claudia Geist, Erin Clouse, Michelle Precourt Debbink, Benjamin Haaland, Amy J. Tanner, and Yoshimi Anzai contributed to this study. The study, "Experiences of a Health System's Faculty, Staff and Trainees Career Development, Work Culture, and Child Care Needs During the COVID-19 Pandemic" appears in JAMA Network Open. It was supported by a Jon M. Huntsman Presidential Endowed Chair awarded to Fagerlin, who is also a research scientist at the VA Salt Lake City Health Care System.

https://www.eurekalert.org/pub_releases/2021-04/uouh-haa033121.php

Real-world Evidence for Improved Outcomes with Histamine Antagonists, Aspirin in COVID-19

 Cameron Mura, Saskia Preissner, Susanne Nahles, Max Heiland, Philip Bourne, Robert Preissner

DOI: 10.21203/rs.3.rs-369927/v1

PDF: https://www.researchsquare.com/article/rs-369927/v1.pdf

COVID-19 has spurred much interest in the therapeutic potential of repurposed drugs, such as acid-reducing drugs that act as histamine H2 receptor antagonists (H2RA). These compounds, exemplified by famotidine (e.g., Pepcid) and ranitidine (e.g., Zantac), bind the H2R and block the histamine-triggered stimulation of signal transduction cascades. Histamine and H2RAs, on the one hand, and downstream physiological pathways, on the other hand, form a dense web of disparate pathways and signaling networks; these networks are ultimately tied to the dysregulated inflammatory cascades (cytokine storm) that underlies the pathophysiology of COVID-19. Is famotidine beneficial in treating COVID-19? This question remains unresolved, despite much recent effort: over 10 studies have examined the potential value of famotidine in COVID-19, but have found largely contradictory results. Given the conflicting reports, we have undertaken a new analysis reported herein, drawing upon a cohort of 22,560 COVID-19 patients. Using electronic health records, we statistically analyzed outcomes for treatment with the H1RAs loratadine (e.g., Claritin) and cetirizine (e.g., Zyrtec), the H2RA famotidine, the general-purpose anti-inflammatory aspirin, and a famotidine & aspirin combination. For severe cases (requiring respiratory support), we found a significantly reduced fatality risk for famotidine treatment. Notably, famotidine combined with aspirin exhibited a significant synergistic survival benefit (odds ratio of 0.55). The relative risk for death decreased by 32.5%—an immense benefit, given the more than 2.6 million COVID-19-related deaths thus far. The large, multi-center retrospective study reported here, sampling over 250,000 COVID-19 cases internationally, hopefully helps clarify the possible value of clinically-approved histamine antagonists such as famotidine. Given these findings, alongside the cost-effectiveness and mild side-effects of common over-the-counter drugs like famotidine and aspirin, we suggest that further prospective clinical trials, perhaps utilizing the aspirin combination reported here, are advisable.

https://www.researchsquare.com/article/rs-369927/v1

 








Functionally distinct coronavirus antibody features in children and elderly

 

  • Kevin J. Selva
  • Carolien E. van de Sandt
  • […]
  • Amy W. Chung 

  • DOI:  https://doi.org/10.1038/s41467-021-22236-7

    Abstract

    The hallmarks of COVID-19 are higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive immunological responses, induced by circulating human coronaviruses (hCoVs), is needed to understand such divergent clinical outcomes. Here we show analysis of coronavirus antibody responses of pre-pandemic healthy children (n = 89), adults (n = 98), elderly (n = 57), and COVID-19 patients (n = 50) by systems serology. Moderate levels of cross-reactive, but non-neutralizing, SARS-CoV-2 antibodies are detected in pre-pandemic healthy individuals. SARS-CoV-2 antigen-specific Fcγ receptor binding accurately distinguishes COVID-19 patients from healthy individuals, suggesting that SARS-CoV-2 infection induces qualitative changes to antibody Fc, enhancing Fcγ receptor engagement. Higher cross-reactive SARS-CoV-2 IgA and IgG are observed in healthy elderly, while healthy children display elevated SARS-CoV-2 IgM, suggesting that children have fewer hCoV exposures, resulting in less-experienced but more polyreactive humoral immunity. Age-dependent analysis of COVID-19 patients, confirms elevated class-switched antibodies in elderly, while children have stronger Fc responses which we demonstrate are functionally different. These insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics.

    https://www.nature.com/articles/s41467-021-22236-7


    Coagulation factors directly cleave SARS-CoV-2 spike, enhance viral entry

     

    Edward R KastenhuberJavier A. JaimesJared L. JohnsonMarisa MercadanteFrauke MueckschYiska WeisblumYaron BramRobert E. SchwartzGary R. WhittakerLewis C. Cantley

    CDC updates guidance to cruise ship industry, urges vax

     The U.S. Centers for Disease Control (CDC) and Prevention on Friday issued new guidance to the cruise ship industry, including the need for COVID-19 vaccinations, a necessary step before passenger voyages can resume.

    The new technical instructions, the first update since October, include increasing from weekly to daily reporting frequency of COVID-19 cases and illnesses and implementing routine testing of all crew based on a ship’s COVID-19 status and establishing a plan and timeline for vaccination of crew and port personnel.

    “COVID-19 vaccination efforts will be critical in the safe resumption of passenger operations,” the CDC said.

    DC said the next phase of the CDC’s conditional sail order will include simulated voyages to will allow crew and port personnel to practice new COVID-19 operational procedures with volunteers before sailing with passengers.

    “CDC is committed to working with the cruise industry and seaport partners to resume cruising when it is safe to do so, following the phased approach outlined” in October’s conditional sail order,” the agency said.

    It did not specify a date for the resumption of cruise operations from U.S. ports despite calls from the industry for planning for a phased resumption by the beginning of July. The CDC said it will issue additional guidance before it will allow cruises to resume.

    The Cruise Lines International Association, which represents Carnival Corp, Norwegian Cruise Line and Royal Caribbean Cruises and others had pleaded with CDC to issue new guidance, saying in a March 24 statement the “lack of any action by the CDC has effectively banned all sailings in the largest cruise market in the world.” It did not immediately comment on Friday.

    The group had said the prior conditional sail order issued in October was “outdated” and “does not reflect the industry’s proven advancements and success operating in other parts of the world, nor the advent of vaccines, and unfairly treats cruises differently. Cruise lines should be treated the same as other travel, tourism, hospitality, and entertainment sectors.”

    https://www.reuters.com/article/us-health-coronavirus-usa-cruises/cdc-updates-guidance-to-cruise-ship-industry-urges-vaccinations-idUSKBN2BP1IY

    Sepsis: Standard of Care Fails While Novel Meds, Diagnostics Go Unused

     Sepsis is among the best-known and least effectively treated conditions in the modern world. The standard of care has failed for these infections, leaving the U.S. healthcare system with $62 billion and 270,000 deaths annually. Globally, 11 million die from sepsis each year.

    Effective drugs and diagnostics are available. They’re just not used, according to panelists at the Demy-Colton Virtual Salon, focused on sepsis.

    “One of the things missing from the sepsis conversation is data. We don’t have the data to advance clinical practice and innovation because it’s siloed among the states (and healthcare systems),” and the players aren’t talking to one another, Thomas Heymann, president and CEO of the Sepsis Alliance, told the Salon audience.

    To provide that data, the Sepsis Alliance launched the National Sepsis National Registry Initiative in January 2021. Its goal is to aggregate and analyze thousands of longitudinal records to gain insights into comorbidities, treatments, and outcomes associated with sepsis.

    Another significant problem is the healthcare reimbursement system, panelists agreed. It relies on blood cultures for diagnoses and, until results are returned – typically one to five days later – doctors prescribe older, generic, broad-spectrum antimicrobial treatments. The alternative is a fast, but more expensive, test that identifies the specific pathogen and the appropriate treatment in less than three hours.

    With sepsis, speed is of the essence. The mortality rate of sepsis patients increases by as much as 8% each hour proper treatment is not started.

    “Sepsis is a community-acquired syndrome,” Heymann said. “It often stems from urinary tract infections and spider bites, for example, but also can be acquired in the hospital. Sepsis is twice as common as stroke, and twice as deadly. The standard of care is failing.”

    The Biomedical Advanced Research and Development Authority (BARDA) invested in – and the FDA approved – new assays to detect and characterize the organisms responsible for sepsis and to identify the most effective drugs, Rick Bright, Ph.D., SVP, pandemic Prevention & response, at Rockefeller Foundation and a former director of BARDA, stressed. “There are amazing diagnostics, but they’re not being used.”

    Bright’s personal experience is an all-too-common case in point. “When I went into urgent care with signs of an infection in my thumb (from gardening), I had to practically beg them to take a culture to identify the organism. They gave me Bactrim and sent me home. I went to the emergency room 10 hours later. They sent me home (with another antibiotic). They didn’t do a blood culture until 6 days later. In the course of 3 days, I was prescribed 7 antibiotics. The hospital said I had a methicillin-resistant staphylococcus aureus (MRSA) infection. Then they scheduled the thumb for amputation.”

    In Bright’s case, the test results arrived before the amputation, enabling an effective therapy to be delivered. It was a branded drug. Then, he said, “I got a note from my insurance company saying it wouldn’t cover the branded antibiotic.”

    “This is the antithesis of precision medicine,” Heymann commented.

    The delay in diagnosis and treatment is the direct result of how hospitals are reimbursed. As Ciara Kennedy, Ph.D., president and CEO of Amplyx Pharmaceuticals, explained, “Hospitals are paid based upon bundled payments for disease codes. For infections, if a patient is given a branded medicine, the hospital loses money. So, generics are first-line therapies.”

    The SEP-1 Early Management Bundle – put in place in 2015 by the Centers for Medicare & Medicaid Services (CMS) – established a protocol to follow when sepsis is suspected. It should have removed that barrier, but didn’t.

    Now what’s needed is “encouraging the doctors not just to perform the test, but to read the test and do what is calls for. That’s where the emphasis should be,” Prabhavathi Fernandes, Ph.D., chair of the scientific advisory board of Global Antibiotic Research & Development Partnership, and chair of the National Biodefense Science Board, said.

    Currently, Kennedy added, “A drug’s value is closely tied to its (sales) volume. The more a drug is used, the greater the return for investors. We need to break that system. Without a system and framework to deliver value, innovation won’t be funded.”

    The Pasteur Act (S.4760)  referred to Committee in 2020, aims to address that. “The Pasteur Act is portrayed as a handout to pharma, but it’s actually a safety net for patients,” she continued. As the bill states, it “authorizes the Department of Health and Human Services (HHS) to enter into subscription contracts for critical-need antimicrobial drugs,” to identify “critical need” antimicrobials, and to develop a list of infections for which innovative antimicrobial treatments are needed.

    The COVID-19 pandemic, in some ways, is bringing attention to sepsis. “There is a clear clinical link between (serious) COVID-19 and sepsis if COVID-19 isn’t treated appropriately,” John Sperzel, III, president and CEO of T2 Biosystems Inc., said.

    Yet, Kennedy added, “There is a misrecognition of what’s killing COVID-19 patients. If a patient dies because of sequelae after COVID-19, they say he or she died of COVID-19.”

    Part of the challenge is that there’s no clear picture of sepsis patients. “Until there is, you don’t connect with them,” she said.

    As a result, panelists noted that many companies go bankrupt after their sepsis diagnostics or therapeutics are approved, and many others have less than six months of cash. Therefore, Kennedy said, “New drugs may not survive because of funding challenges.”

    The long-term consequences are serious. Many sepsis patients never fully recover, leading to chronic conditions and greater susceptibility to subsequent sepsis infections that, often, lead to death. More work to characterize the organisms early on, combined with administration of the proper drug – perhaps based upon biomarkers and computer-aided diagnosis, could go a long way to resolving the problem. “If you don’t think about sepsis, you don’t treat it,” Bright said.

    Education and deeper understanding are critical to successfully diagnosing and treating sepsis. As Fernandes concluded, “It's important to understand that every infection, until it goes away, can become serious.”

    https://www.biospace.com/article/sepsis-standard-of-care-fails-while-novel-meds-and-diagnostics-go-unused/