Antiviral effect of high-dose ivermectin in adults with COVID-19

 

• Alejandro Krolewiecki
• Adrián Lifschitz
• Matías Moragas
• Marina Travacio
• Ricardo Valentini
• Daniel F. Alonso
• et al.

DOI:https://doi.org/10.1016/j.eclinm.2021.100959

PDF: https://www.thelancet.com/action/showPdf?pii=S2589-5370%2821%2900239-X

Abstract

Background

There are limited antiviral options for the treatment of patients with COVID-19. Ivermectin (IVM), a macrocyclic lactone with a wide anti-parasitary spectrum, has shown potent activity against SARS-CoV-2 in vitro. This study aimed at assessing the antiviral effect of IVM on viral load of respiratory secretions and its relationship with drug concentrations in plasma.

Methods

Proof-of-concept, pilot, randomized, controlled, outcome-assessor blinded trial to evaluate antiviral activity of high-dose IVM in 45 COVID-19 hospitalized patients randomized in a 2:1 ratio to standard of care plus oral IVM at 0·6 mg/kg/day for 5 days versus standard of care in 4 hospitals in Argentina. Eligible patients were adults with RT-PCR confirmed SARS-CoV-2 infection within 5 days of symptoms onset. The primary endpoint was the difference in viral load in respiratory secretions between baseline and day-5, by quantitative RT-PCR. Concentrations of IVM in plasma were measured. Study registered at ClinicalTrials.gov: NCT04381884.

Findings

45 participants were recruited (30 to IVM and 15 controls) between May 18 and September 9, 2020. There was no difference in viral load reduction between groups but a significant difference was found in patients with higher median plasma IVM levels (72% IQR 59–77) versus untreated controls (42% IQR 31–73) (p = 0·004). Mean ivermectin plasma concentration levels correlated with viral decay rate (r: 0·47, p = 0·02). Adverse events were similar between groups. No differences in clinical evolution at day-7 and day-30 between groups were observed.

Interpretation

A concentration dependent antiviral activity of oral high-dose IVM was identified at a dosing regimen that was well tolerated. Large trials with clinical endpoints are necessary to determine the clinical utility of IVM in COVID-19.

Funding

This work was supported by grant IP-COVID-19-625, Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación, Argentina and Laboratorio ELEA/Phoenix, Argentina.

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00239-X/fulltext

Telmisartan for treatment of Covid-19 patients

 

• Mariano Duarte 1
• Facundo Pelorosso 1
• Liliana N. Nicolosi 1
• M. Victoria Salgado
• Héctor Vetulli
• Analía Aquieri
• et et al

DOI:https://doi.org/10.1016/j.eclinm.2021.100962

PDF: https://www.thelancet.com/action/showPdf?pii=S2589-5370%2821%2900242-X

Abstract

Background

Angiotensin receptor blockers (ARBs), such as telmisartan, have been postulated to treat Covid-19-induced lung inflammation.

Methods

This is a parallel-group, randomized, two-arm, open-label, adaptive, multicenter superiority trial with 1:1 allocation ratio. Participants included patients from 18 years of age hospitalized with Covid-19 with 4 or fewer days since symptom onset enrolled at a university and a community hospital in Buenos Aires, Argentina. Exclusion criteria included prior intensive care unit (ICU) admission and use of ARBs/angiotensin converting enzyme inhibitors at randomization. Control arm received standard care alone and treatment arm telmisartan 80 mg twice daily for 14 days. Primary outcomes were C-reactive protein (CRP) plasma levels at day 5 and 8 after randomization. Secondary outcomes included time to discharge within 15 days, admission to ICU and death at 15- and 30-days. NCT04355936 (Completed).

Findings

A pragmatic decision to end the study before the third interim analysis was made on Oct. 30th due to sharp reduction in recruitment. A total of 162 patients were randomized. 158 patients enrolled between May 14 and October 30 2020, were included in the analysis, 80 in the standard care and 78 in the telmisartan added to standard care group. Baseline absolute CRP serum levels were 5.53 ± 6.19 mg/dL (95% CI 6.91 to 4.15, n = 80) and 9.04 ± 7.69 (95% CI 9.04 to 10.82, n = 74) in the standard care and telmisartan added to standard care groups, respectively. Day 5 control-group CRP levels were 6.06 ± 6.95 mg/dL (95% CI 7.79–4.35, n = 66) while telmisartan group were 3.83 ± 5.08 mg/dL (95% CI 5.08–2.59, n = 66, p = 0.038). Day 8 CRP levels were 6.30 ± 8.19 mg/dL (95% CI 8.79–3.81, n = 44) and 2.37 ± 3.47 mg/dL (95% CI 3.44–1.30, n = 43, p = 0.0098) in the control and telmisartan groups, respectively (all values expressed as mean ± SD). Kaplan-Meier analysis showed that telmisartan-treated patients had a lower median time-to-discharge (control=15 days; telmisartan=9 days). Death by day 30 was reduced in the telmisartan-treated group (control 22.54%, 16/71; telmisartan 4.29%, 3/70 participants; p = 0.0023). Composite ICU, mechanical ventilation or death was reduced by telmisartan treatment at days 15 and 30. No adverse events were reported.

Interpretation

Our study suggests that the ARB telmisartan, a widely used antihypertensive drug, is safe and could reduce morbidity and mortality in hospitalized patients infected with SARS -CoV-2 by anti-inflammatory effects. Further studies employing telmisartan are needed for confirmation of our results and to define its true therapeutic value as a tool against Covid-19.

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00242-X/fulltext#%20

Reviewing data on reputed toxins thought to cause neurodegeneration

 Identifying the causes of human neurodegenerative diseases is a global research priority, warranting frequent reviews of the accumulating knowledge. In doing just that, biologists from the Plant Physiology Laboratory at the University of Guam and neuroscientists from the Experimental Medicine Program at The University of British Columbia have published an update on the reputed environmental toxins that have been suspected of being involved in mammal neurodegeneration. Their summary was published in April in the book Spectrums of Amyotrophic Lateral Sclerosis, which is available online from the publisher Wiley Blackwell.

A decades-long search for a dementia-causing toxin

Interest in the correlations between environmental toxins and neurodegeneration focused the world's magnifying glass on the island of Guam in the 1950s due to an unexpected increase in cases of neurodegenerative cases among the indigenous CHamoru population. The specific condition that temporarily affected Guam is known as amyotrophic lateral sclerosis-parkinsonism dementia (ALS-PDC) and known locally by the CHamoru term lytico-bodig.

A focus on this isolated cluster of cases led to decades of pursuit of causal toxins found in seeds of Guam's native cycad tree. These seeds were components of the local cuisine at the time, and increased reliance on this form of food starch during World War II was a plausible hypothesis to explain the increase in neurodegeneration cases shortly after the war.

Several factors likely coalesce

An ebb and flow of sequential disappointments has evolved since the 1950s because the identification of a single causal cycad toxin remains elusive.

But these disappointments have been countered by successes. It is now understood that several factors likely coalesce into a synchronized perfect storm to generate an unusual increase in localized neurodegenerative cases, such as what temporarily happened on Guam. These co-factors may include exposure to high doses of the environmental toxin by the most susceptible gender with the most susceptible genes at the most susceptible age, followed by a latency period before the neuronal damage begins to express itself.

The UOG-UBC collaboration has lasted more than two decades, and various members of the team have authored more than 100 journal articles on various aspects of cycad biology during that time. The toxicology of Guam cycad seeds was the subject of 14 of these publications.

"When I began collaborating with UOG, we had the benefit of building on the foundation of decades of research from Guam," said co-author Christopher Shaw, UBC neuroscientist. "We used the fact that no plant scientist had been directly involved in any of the previously published research to secure funds to revisit various issues concerning cycad seed toxins."

Difference between acute and slow-acting toxins

One of the many confusing aspects of this research is that acute toxins, which cause immediate poison reactions following cycad seed ingestion, are distinct from slow-acting toxins, which lead to neurodegeneration.

"The distinctions between these two forms of toxins are often confused, and scientists are constantly reminding the public that many years need to elapse after the exposure to a slow plant toxin before negative health outcomes develop," said Benjamin Deloso, a cycad biologist with UOG.

Claims of cyanide poisoning inaccurate

Another benefit from the marathon pursuit of the causal cycad toxin is that an enormous body of literature has developed that uncovered which biomolecules are not at play. "This is how science works," Shaw said. "The aggressive empirical look at each candidate toxin was justified and refined the development of superseding hypotheses that were vigorously tested."

For example, cassava roots contain sugar-based molecules that liberate cyanide after ingestion by mammals, and cycad seeds contain similar molecules, but cycad seeds contain no free cyanide and the identified sugar-based cycad molecules in cycads are incapable of liberating toxic levels of cyanide following ingestion by mammals. The meticulous research revealed the claims of cyanide as a potential cycad toxin and that cycad seed consumption could cause cyanide poisoning were inaccurate.

"Throwing around fear-mongering buzzwords, like cyanide, is a classic example of a repetition of false information in order to drive a personal agenda," Deloso said. "There are even petitions being circulated that falsely claim that cycad plants contain cyanide in attempts to force retail nurseries to stop selling cycad plants to pet owners."

The research team contends that scientists are not immune from the mistake of repeating these sorts of false claims about cycads. This tends to happen when scientists get their information from the gray literature or online encyclopedia style websites that are not vetted by cycad experts.

The authors hope that one outcome of their new publication is a decline in the spread of false information about cycad poisoning, as these untruthful statements damage the international community's attempts to improve cycad conservation.

Story Source:

Materials provided by University of Guam. Note: Content may be edited for style and length.

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Journal Reference:

1. Christopher A. Shaw, Thomas E. Marler. The Lessons of ALS‐PDC – Environmental Factors in ALS Etiology. Spectrums of Amyotrophic Lateral Sclerosis, 2021 DOI: 10.1002/9781119745532.ch4

https://www.sciencedaily.com/releases/2021/06/210618134046.htm

Human cells can write RNA sequences into DNA

 Cells contain machinery that duplicates DNA into a new set that goes into a newly formed cell. That same class of machines, called polymerases, also build RNA messages, which are like notes copied from the central DNA repository of recipes, so they can be read more efficiently into proteins. But polymerases were thought to only work in one direction DNA into DNA or RNA. This prevents RNA messages from being rewritten back into the master recipe book of genomic DNA. Now, Thomas Jefferson University researchers provide the first evidence that RNA segments can be written back into DNA, which potentially challenges the central dogma in biology and could have wide implications affecting many fields of biology.

"This work opens the door to many other studies that will help us understand the significance of having a mechanism for converting RNA messages into DNA in our own cells," says Richard Pomerantz, PhD, associate professor of biochemistry and molecular biology at Thomas Jefferson University. "The reality that a human polymerase can do this with high efficiency, raises many questions." For example, this finding suggests that RNA messages can be used as templates for repairing or re-writing genomic DNA.

The work was published June 11th in the journal Science Advances.

Together with first author Gurushankar Chandramouly and other collaborators, Dr. Pomerantz's team started by investigating one very unusual polymerase, called polymerase theta. Of the 14 DNA polymerases in mammalian cells, only three do the bulk of the work of duplicating the entire genome to prepare for cell division. The remaining 11 are mostly involved in detecting and making repairs when there's a break or error in the DNA strands. Polymerase theta repairs DNA, but is very error-prone and makes many errors or mutations. The researchers therefore noticed that some of polymerase theta's "bad" qualities were ones it shared with another cellular machine, albeit one more common in viruses -- the reverse transcriptase. Like Pol theta, HIV reverse transcriptase acts as a DNA polymerase, but can also bind RNA and read RNA back into a DNA strand.

In a series of elegant experiments, the researchers tested polymerase theta against the reverse transcriptase from HIV, which is one of the best studied of its kind. They showed that polymerase theta was capable of converting RNA messages into DNA, which it did as well as HIV reverse transcriptase, and that it actually did a better job than when duplicating DNA to DNA. Polymerase theta was more efficient and introduced fewer errors when using an RNA template to write new DNA messages, than when duplicating DNA into DNA, suggesting that this function could be its primary purpose in the cell.

The group collaborated with Dr. Xiaojiang S. Chen's lab at USC and used x-ray crystallography to define the structure and found that this molecule was able to change shape in order to accommodate the more bulky RNA molecule -- a feat unique among polymerases.

"Our research suggests that polymerase theta's main function is to act as a reverse transcriptase," says Dr. Pomerantz. "In healthy cells, the purpose of this molecule may be toward RNA-mediated DNA repair. In unhealthy cells, such as cancer cells, polymerase theta is highly expressed and promotes cancer cell growth and drug resistance. It will be exciting to further understand how polymerase theta's activity on RNA contributes to DNA repair and cancer-cell proliferation."

This research was supported by NIH grants 1R01GM130889-01 and 1R01GM137124-01, and R01CA197506 and R01CA240392. This research was also supported in part by a Tower Cancer Research Foundation grant.

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Story Source:

Materials provided by Thomas Jefferson University. Note: Content may be edited for style and length.

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Journal Reference:

1. Gurushankar Chandramouly, Jiemin Zhao, Shane McDevitt, Timur Rusanov, Trung Hoang, Nikita Borisonnik, Taylor Treddinick, Felicia Wednesday Lopezcolorado, Tatiana Kent, Labiba A. Siddique, Joseph Mallon, Jacklyn Huhn, Zainab Shoda, Ekaterina Kashkina, Alessandra Brambati, Jeremy M. Stark, Xiaojiang S. Chen, Richard T. Pomerantz. Polθ reverse transcribes RNA and promotes RNA-templated DNA repair. Science Advances, 2021; 7 (24): eabf1771 DOI: 10.1126/sciadv.abf1771

https://www.sciencedaily.com/releases/2021/06/210611174037.htm

3D bioprinting can help end organ transplant waitlists — if FDA stops delaying

 Right now, more than 100,000 Americans are waiting for organ transplants. Due to a lack of available kidneys, livers, hearts, and lungs, at least 17 of them die each day.

Using 3D bioprinting to create new organs — and personalize them for recipients — could prevent these tragic deaths. Yet inaction at the Food and Drug Administration is impeding the rollout of this technology. Regulators have not yet come up with a framework for reviewing and approving these lab-grown organs. Until they do, Americans awaiting organ transplants will continue to suffer.

These people already face long odds. A willing donor must die or, in the case of kidney transplants, a living donor must agree to a major procedure. Donors’ organs need to match the potential recipients’ blood types and body sizes. Because many organs can only be preserved for hours, potential recipients need to stay near hospitals so they can undergo transplantation at a moment’s notice. And the organ must be delivered on time to the recipient.

No wonder so many people languish for years on transplant wait lists.

And for those lucky enough to secure an organ transplant, there’s no guarantee of success. By one estimate, around half of new organs are rejected by recipients’ bodies within 10 to 12 years.

3D bioprinting can help overcome these challenges.

The process involves printing human tissue layer by layer using cells that are genetically identical to those of the recipient. Scientists harvest these cells from a transplant recipient and grow them in the lab. They then use a 3D printer to arrange those cells to create the tissue the patient needs.

This technology looks more promising by the day. Fifteen years ago, Anthony Atala and his team at Wake Forest University made history by successfully transplanting a lab-grown human bladder into a patient.

A new documentary called “They Say It Can’t Be Done” highlights the real-world impact of this technology. The film features Luke Massella, one of the first people to receive a lab-grown human bladder. Atala’s invention allowed Massella to have a high school sports career, graduate, and attend college instead of remaining on dialysis for the rest of his life.

More recently, researchers at Carnegie Mellon University have found a way to bioprint full-scale components of the human heart. Last month, a team at Lund University in Sweden announced a new “bioink” that can be used to print lung tissue.

Scientists are eager to turn this cutting-edge research into tangible, widely available solutions. But they are running into regulatory barriers at the FDA.

The FDA was established to handle mass-market products like drugs and medical devices that can be evaluated through a systematic process of clinical trials. Its statutory framework and traditional approach don’t mesh neatly with a technology as unprecedented as 3D bioprinting.

Determining the safety and efficacy of 3D printed organs requires a different approach than the FDA is used to. Instead of being mass-produced therapies, bioprinted organs are one-of-a-kind creations, tailor-made for each patient. This fact alone warrants new standards, procedures, and guidelines.

In 2017, the FDA announced its intention “to review the regulatory issues related to the bioprinting of biological, cellular, and tissue-based products to determine whether additional guidance is needed.” So far, though, such guidance has not yet materialized.

The agency’s failure to act is a major impediment to this lifesaving innovation. Turning a promising scientific discovery into a real-world medical treatment almost always requires large amounts of private funding. Even in the best of circumstances, the risks of investing in an unproven technology are considerable. Those risks become impossibly high in the absence of a framework for regulating this new technology and bringing it to market.

For 3D bioprinting technology to reach its full potential, billions of investment dollars will be needed. That will be possible only if the FDA provides clear, predictable rules and standards for this new area of medicine.

3D bioprinting represents an excellent chance of helping end the organ shortage. Potential transplant recipients shouldn’t perish on waitlists while the needed guidance for this technology languishes in regulators’ inboxes.

Dan Troy is the executive vice president and general counsel of Boston-based Valo Health, cochair of the Regulatory Transparency Project’s FDA and Health Group, and a former chief counsel for the FDA. The opinions expressed here do not represent the views of any company he is affiliated with, and he reports no financial interest relating to organ bioprinting.

https://www.statnews.com/2021/06/18/3d-bioprinting-organ-transplant-waitlists-fda-delay/

New Covid study hints at long-term loss of brain tissue: Gottlieb

 Dr. Scott Gottlieb warned Thursday about the potential for long-term brain loss associated with Covid, citing a new study from the United Kingdom.

“In short, the study suggests that there could be some long-term loss of brain tissue from Covid, and that would have some long-term consequences,” the former FDA chief and CNBC contributor said. 

 “You could compensate for that over time, so the symptoms of that may go away, but you’re never going to regain the tissue if, in fact, it’s being destroyed as a result of the virus,” said Gottlieb, who serves on the board of Covid vaccine-maker Pfizer.

The U.K. study examined brain imaging before and after a coronavirus infection and looked specifically at the potential effect on the nervous system. 

Gottlieb explained to CNBC’s “The News with Shepard Smith” that the destruction of brain tissue could explain why Covid patients lost their sense of smell. 

“The diminishment in the amount of cortical tissue happened to be in regions of the brain that are close to the places that are responsible for smell,” he said. “What it suggests is that, the smell, the loss of smell, is just an effect of a more primary process that’s underway, and that process is actually shrinking of cortical tissue.” 

Disclosure: Scott Gottlieb is a CNBC contributor and is a member of the boards of Pfizer, genetic testing start-up Tempus, health-care tech company Aetion Inc. and biotech company Illumina.

https://www.cnbc.com/2021/06/17/new-covid-study-hints-at-long-term-loss-of-brain-tissue-dr-scott-gottlieb-warns.html

Tokyo scraps public viewing of Olympics

 Authorities have canceled all public viewing events to reduce the risk of coronavirus infections at a time when Japan is struggling to speed up its inoculation efforts.

Tokyo Governor Yuriko Koike said on Saturday that the city administration is canceling all public viewing events in the Japanese capital to prevent the risk of a surge in coronavirus infections.  

"These are necessary measures to make the Tokyo Olympics and Paralympics a success,'' she told reporters after meeting with Japanese Prime Minister Yoshihide Suga.

There had been six planned viewing sites across the Japanese capital, including Inokashira and Yoyogi parks as well as a university in Tokyo.

Koike said the sites will now instead be offered as COVID vaccination centers.

Holding Games behind closed doors?

The announcement came as Koike and Suga prepare for a key meeting with Olympics and Paralympics officials on Monday.

They are then expected to finalize whether to allow domestic spectators inside Games venues.

Politicians and organizers are pushing for some spectators to be allowed. But public health experts have recommended holding the Games behind closed doors.

Fans from abroad were already banned several months ago.

Officials have also reduced the number of participants, volunteers and guests.

Even though authorities are forging ahead with hosting the Games from July 23, various public opinion polls show most Japanese are opposed to holding the event.

https://www.dw.com/en/covid-tokyo-scraps-public-viewing-of-olympics/a-57964417