cytokine storm Archives - Amazing Health Advances

New COVID-19 Drug Passes Phase 2 Clinical Trial

AHA Publisher — Thu, 20 Jan 2022 08:00:34 +0000

Sanford Burnham Prebys via Newswise – LA JOLLA, CALIF. – Jan 18, 2021 – In a phase 2 clinical trial conducted by Avalo Therapeutics and supported by researchers from Sanford Burnham Prebys, a significantly higher proportion of hospitalized patients with COVID-19 remained alive and free of respiratory failure for 28 days after receiving treatment with a new antibody called CERC-002. Unlike other experimental COVID therapies, CERC-002 does not target the virus itself, instead targeting the immune response associated with the virus to stop the disease from progressing before it becomes fatal. “At the beginning of the pandemic we thought vaccines were going to be all we really needed. But with variants like omicron, we’re going to have more people that progress to serious illness even with the vaccine,” says study coauthor Carl F. Ware, Ph.D., director of the Infectious and Inflammatory Diseases Center at Sanford Burnham Prebys. “We need treatments to stop the progression to severe disease and death.” The findings were published December 6 in the Journal of Clinical Investigation. COVID-19: a Continuing Crisis In the United States, over 800,000 people have died from COVID-19. A large proportion of these deaths have been among the elderly or those who are immunocompromised due to a preexisting condition. And while three quarters of the population has received at least one dose of the COVID-19 vaccine, many remain unvaccinated. “A lot of us feel safer now that we’ve gotten our shots,” Ware says, “but the threat of the pandemic has not gone away, even for vaccinated people.” Most people with COVID-19 experience few to no symptoms. However, elderly individuals, people with a concurrent health condition or those who are immunocompromised are susceptible to a condition called cytokine storm, in which their own immune molecules called cytokines flood the body in higher concentrations than usual. Rather than helping fight the virus, these extra immune molecules wreak havoc, causing patients to develop the deadly respiratory failure characteristic of severe COVID disease. “The COVID virus gets the immune system amped up by producing these molecules, which is normally how the immune system fights diseases,” says Ware. “But when there are too many cytokines and they’re not doing their job, it can lead to severe damage.” Neutralizing the Cytokine Storm The new treatment, CERC-002, is a cytokine neutralizer—an immune molecule that recognizes and deactivates a cytokine known as LIGHT, which is elevated in patients with COVID-19. Cytokine neutralization drugs are currently being tested in the clinic, but they are mainly effective in severely ill patients who are already on a ventilator or other organ support. “There is a critical need for drugs to stop milder cases from progressing to severe,” says Ware. “This treatment targets the cytokine immune response early enough to stop it in its tracks, which no other treatment does right now.” 83 COVID patients were enrolled in the study, half receiving the treatment, and half receiving a placebo. All patients were hospitalized with mild-to-moderate respiratory distress and were also receiving standard-of-care therapy during the trial. They found that 83.9% of patients who received a dose of CERC-002 on top of standard of care remained alive and free from respiratory distress for 28 days. For patients receiving placebo, the number was only 64.5%. Looking Ahead As a phase 2 clinical trial, the purpose of this study was to test whether the compound has therapeutic potential in a small number of patients. Now that the drug has proven successful at a small scale, it can be tested on a larger number of patients to ensure its benefits are consistent across the population. Additionally, because CEC-002 targets the immune response in COVID cases rather than the virus itself, the compound may have applications that extend beyond COVID. “Cytokine storm is not unique to COVID. It occurs in other infections—even in autoimmune diseases with no active infection, so this treatment may have some utility in these other diseases as well.” While there is more work to be done before CERC-002 becomes widely available, it does offer a glimmer of hope during a pandemic that seems never-ending. “We have made a lot of progress in controlling the pandemic with vaccines and other new therapies, but it’s not over yet,” says Ware. “Treatments like this may bring physicians an option to protect infected people from severe illness. To read the original article click here.

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Over-the-Counter Acid Reflux Drug Appears to Improve the Odds of Survival for COVID-19 Patients

AHA Publisher — Mon, 23 Aug 2021 07:00:11 +0000

University of Virginia School of Engineering and Applied Science via News Medical – In the early days of the COVID-19 pandemic, doctors in Wuhan noticed something surprising. Many of the elderly patients who survived the virus were poor: not exactly the demographic you would expect to fare well in a health crisis. A review of the survivors’ medical records revealed that a significant number suffered from chronic heartburn and were taking an inexpensive drug called famotidine, the key ingredient in Pepcid. (Wealthier patients tended to take the more costly drug omeprazole, found in Prilosec.) Was an over-the-counter acid suppressant helping people survive COVID-19? This is how many medical studies begin, said biomedical engineering professor Phil Bourne, who serves as founding dean for the School of Data Science. “There’s often a phenomenon that doctors report anecdotally, or that’s mentioned in passing in a particular research paper, and that provides a clue -; a hook,” he said. Typically, to find out whether a drug is effective in treating a particular medical condition, scientists develop prospective clinical trials. But this method is expensive and can take years, Bourne pointed out. When faced with a global pandemic, it’s helpful to explore other options. That’s where data scientists come in. Bourne and UVA senior scientist Cameron Mura worked with an international team of researchers to analyze information from a database that holds the medical records of millions of COVID-19 patients living in 30 different countries. The team winnowed that number down to around 22,000 people, the largest sample size for a study on famotidine and the disease to date. “The power of the electronic health record, which is really yet to be fully realized as a research tool, is that you’ve suddenly got all this data you can mine to see whether what you determined in passing or anecdotally has any basis.” Phil Bourne, Biomedical Engineering Professor The team’s analysis, which appeared in the journal Signal Transduction & Targeted Therapy(from the Nature publishing group), showed that the data supported findings from other smaller-scale studies. When delivered at high doses (the equivalent of about 10 Pepcid tablets), famotidine appears to improve the odds of survival for COVID-19 patients, especially when it is combined with aspirin. It also seems to hinder the severity of disease progression, making patients less likely to reach the point where they require intubation or a ventilator. The next challenge was to figure out why. Data scientists like Mura and Bourne perform extensive detective work for medical analyses like this one, looking at existing information and drawing upon biochemical and molecular principles to propose a cohesive theory that helps elucidate the population-scale patterns they identify. Mura calls this “weaving a story” based on the data. He needed to work backwards from massive groups of people and draw some possible conclusions about what was happening at a totally different scale -; the scale of proteins that are “one millionth the size of an ant,” he said. One of the most dangerous phenomena COVID-19 can trigger in your body is something called a cytokine storm, which is a potentially fatal amplification of an immune response. When you become sick, your immune system releases inflammatory proteins called cytokines that tell your immune cells how to fight the infection. But in more severe illnesses, cytokine production can spiral out of control, becoming dysregulated. “Basically, your immune system goes haywire and starts attacking things like your otherwise healthy lung tissue because it’s so desperate to kill off the invading virus,” Mura said. “Your own physiology essentially uses a sledgehammer against the pathogen when a fly swatter would suffice.” The team’s theory is that famotidine suppresses that reaction. Although it was developed with a specific purpose in mind -; blocking the histamine receptors that help produce acid in your stomach -; famotidine, like all other medications, can cause side effects. Mura and his colleagues believe that interfering with cytokine storms might be one of them. “It may well be a case of famotidine having a beneficial off-target effect,” Mura said. We generally think of side effects as a bad thing, but in some cases, they can be harnessed to treat other conditions. In the future, it’s possible that famotidine could be re-purposed in this way. But the team’s findings are far from conclusive. Other studies have offered conflicting pictures of what famotidine can do for COVID-19 patients: Some have found that it has a neutral effect and one has even suggested that it might be detrimental. Mura, Bourne and their colleagues recently published a review of existing research on the subject, along with suggestions for a framework that could help reconcile the contradictory reports. Still, with its unique focus on combining famotidine with aspirin and its impressively large sample size, the team’s study has shed further light on an inexpensive and safe potential treatment that would be easy for doctors to prescribe. In the midst of an international health crisis, the study has also laid important groundwork for further research. “Scientific studies are sometimes viewed as the end-all, be-all, but they’re really just a starting point or a springboard,” Mura said. “Any good study raises more questions than it answers, and data science is often what kick-starts that process.” To read the original article click here.

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Cannabis Compound Inhibits SARS-CoV-2 Replication in Human Lung Cells

AHA Publisher — Mon, 22 Mar 2021 07:00:34 +0000

Sally Robertson, B.Sc. via New-Medical – Researchers in the United States have conducted a study showing that a cannabis plant compound inhibited infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human lung cells. SARS-CoV-2 is the agent responsible for the coronavirus disease 2019 (COVID-19) pandemic that continues to sweep the globe posing a threat to global public health and the worldwide economy. Marsha Rosner from the University of Chicago in Illinois and colleagues found that cannabidiol (CBD) and its metabolite 7-OH-CBD potently blocked SARS-CoV-2 replication in lung epithelial cells. The CBD inhibited viral gene expression and reversed many of the effects the virus has on host gene transcription. The compound also induced the expression of interferons – cell signaling proteins that are produced by host cells as an early response to viral invasion. Furthermore, the incidence of SARS-CoV-2 infection was up to an order of magnitude lower in a cohort of patients who had been taking CBD, compared with matched patients who had not been taking CBD. “This study highlights CBD, and its active metabolite, 7-OH-CBD, as potential preventative agents and therapeutic treatments for SARS-CoV-2 at early stages of infection,” says Rosner and the team. A pre-print version of the research paper is available on the bioRxiv* server, while the article undergoes peer review. Rapid Spread of SARS-CoV-2 Highlights the Need for New Treatments Since the COVID-19 outbreak first began in Wuhan, China, in late December 2019, the rapid spread of SARS-CoV-2 has led to more than 119.5 million infections and caused more than 2.64 million deaths. Although recently-approved vaccines are now being rolled out in many countries, the virus is still spreading rapidly. Rosner and colleagues say this highlights the need for alternative approaches, particularly among populations with limited access to vaccines. However, “to date, few therapies have been identified that block SARS-CoV-2 replication and viral production,” write the researchers. More About SARS-CoV-2 and CBD The SARS-CoV-2 virus primarily enters host cells through the binding of a surface viral protein called spike to the human host cell receptor angiotensin-converting enzyme 2 (ACE2). The viral genome is then translated into two large polypeptides that are cleaved by the viral proteases MPro and PLPro to produce the proteins required for viral replication, assembly, and budding. Rosner and colleagues say that, although limited, some studies have reported that certain cannabinoids have antiviral effects against hepatitis C virus and other viruses. Furthermore, an oral solution of CBD is already approved by the US food and Drug Administration for the treatment of epilepsy. What Did the Current Study Involve? To test the effect of CBD on SARS-CoV-2 replication, the researchers pretreated A549 human lung carcinoma cells expressing ACE-2 (A549-ACE2) with 0-10μM CBD for 2 hours before infecting them with SARS-CoV-2. Analysis of the cells 48 hours later showed that CBD had potently inhibited viral replication in the cells. Since CBD is often consumed as part of a Cannabis sativa extract, the team investigated whether other cannabinoids could also inhibit SARS-CoV-2 infection, especially those with closely related structures. Remarkably, the only agent that potently inhibited viral replication was CBD; limited or no antiviral activity was exhibited by the other structurally similar cannabinoids tested. Furthermore, the CBD metabolite 7-OH-CBD, the active ingredient in the CBD treatment of epilepsy, also effectively inhibited SARS-CoV-2 replication in the A549-ACE2 cells. CBD Effectively Eliminated Viral RNA Expression When the researchers assessed whether CBD might prevent proteolytic cleavage by Mpro or PLpro, they found CBD had no effect on the activity of either protease. This led the team to hypothesize that CBD targets host cell processes. Consistent with this hypothesis, RNA sequencing of infected A549-ACE2 cells treated with CBD for 24 hours revealed significant suppression of SARS-CoV-2-induced changes in gene expression. The CBD effectively eliminated viral RNA expression, including RNA coding for the spike protein. Both SARS-CoV-2 and CBD triggered significant changes in cellular gene expression, including the expression of several transcription factors. Further analysis of host cell RNA showed that the virus-induced changes were almost completely reversed, but rather than the cells returning to a normal cell state, the CBD+virus-infected cells resembled those treated with CBD alone. What About Interferon Signaling? Given that infection with SARS-CoV-2 is known to suppress the interferon signaling pathway, the researchers tested whether CBD could suppress viral infection by introducing this pathway. Some genes were induced by CBD in both the absence and presence of SARS-CoV-2, including genes that encode interferon receptors and mediators of the interferon signaling pathway. In addition, CBD effectively reversed the viral induction of cytokines that can trigger a deadly hyperinflammatory response called the “cytokine storm” during the later stages of infection. “Thus, CBD has the potential not only to act as an antiviral agent at early stages of infection but also to protect the host against an overactive immune system at later stages,” says Rosner and the team. SARS-CoV-2 Incidence Was Lower in Patients Who Took CBD Finally, the team assessed the incidence of SARS-CoV-2 infection among 82 patients who had been prescribed CBD prior to SARS-C0V-2 testing and matched patients who had not been prescribed CBD. Strikingly, the incidence of SARS-CoV-2 was only 1.2% among the patients prescribed CBD, compared with 12.2% among the matched patients who had not been taking CBD. “The substantial reduction in SARS-CoV-2 infection risk of approximately an order of magnitude in patients who took FDA-approved CBD highlights the potential efficacy of this drug in combating SARS-CoV2 infection,” says Rosner and colleagues. “We advocate carefully designed placebo-controlled clinical trials with known concentrations and highly-characterized formulations in order to define CBD’s role in preventing and treating early SARS-CoV-2 infection,” they conclude. *Important Notice bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information. To read the original article click here.

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Has Israel Just Found the Cure for Covid?

AHA Publisher — Tue, 09 Feb 2021 08:00:39 +0000

Abigail Klein Leichman via Israel21c – Even with Israel’s world-leading rollout of Covid-19 vaccinations, drugs to treat Covid patients are in desperate need across the world. Two such drugs developed in Israel show great promise in clinical trials: EXO-CD24 and Allocetra. EXO-CD24, an experimental inhaled medication developed at Tel Aviv Sourasky Medical Center, cured all 30 moderate-to-severe cases in a Phase I clinical trial. Developed over the past six months at the hospital, EXOCD24 stops the “cytokine storm” – where the immune system goes out of control and starts attacking healthy cells – that occurs in the lungs of 5-7% of Covid-19 patients. “To date, the preparation has been tried with great success on 30 severe patients, in 29 of whom the medical condition improved within two to three days and most of them were discharged home within three to five days. The 30th patient also recovered but after a longer time,” the hospital reports. “The drug is based on exosomes, [vesicles] that are released from the cell membrane and used for intercellular communication. We enrich the exosomes with 24CD protein. This protein is expressed on the surface of the cell and has a known and important role in regulating the immune system,” explained Dr. Shiran Shapira, director of the laboratory of Prof. Nadir Arber, who has been researching the CD24 protein for over two decades. “The preparation is given by inhalation, once a day, for only a few minutes, for five days,” Shapira said. She said the experimental treatment has two unique characteristics. The first is that it inhibits the over-secretion of cytokines. The second is that it is delivered directly to the lungs and therefore has no systemic side effects that injected or oral drugs can cause. “Even if the vaccines perform their function, and even if no new mutations are produced then still in one way or another the corona will remain with us,” said Arber, director of the medical center’s Integrated Cancer Prevention Center. “To this end, we have developed a unique drug, EXO-CD24.” Arber added that this advanced preparation “can be produced quickly and efficiently and at a very low cost in every pharmaceutical facility in the country, and in a short time globally.” Prof. Ronni Gamzu, CEO of the medical center, said, “Prof. Arber’s results for first-phase research were excellent and gave us all confidence in the method he has been researching [here] for many years. I personally assisted him in further obtaining the approvals from the Ministry of Health for further research.” Allocetra Meanwhile, Enlivex Therapeutics last week reported positive results from a multi-center Phase II clinical trial of its experimental Covid-19 immunotherapy drug Allocetra in severe and critical Covid-19 patients. We reported in October that five Covid-19 intensive care patients were discharged from Hadassah University Medical Center in Jerusalem after treatment with Allocetra. Nine severe and seven critical Covid-19 patients were treated with Allocetra in the Phase II clinical trial. Fourteen of them recovered and were discharged from the hospital after an average of 5.3 days. The Phase II trial originally was expected to enroll 24 patients but was “completed early in support of anticipated accelerated regulatory filings of the trial’s positive safety and efficacy data,” Enlivex reported. Altogether, 19 out of 21 Phase II and Phase Ib Allocetra trial patients recovered and were discharged from the hospital after an average of 5.6 days. Most of the patients in both studies had pre-existing risk factors such as male gender, obesity and hypertension. “The results we have seen from the 12 Covid-19 patients treated to date with Allocetra are exciting,” said Prof. Vernon van Heerden, head of the General Intensive Care Unit at Hadassah and the lead investigator of both clinical trials. “The Phase II patients who have been discharged from the hospital are currently healthy. We believe that these compelling results have demonstrated the safety and efficacy of Allocetra in these complicated patients, highlighting the potential of Enlivex’s product candidate to benefit severe and critical Covid-19 patients as well as others suffering from cytokine storms and organ dysfunctions across various clinical indications.” Allocetra is based on the research of Enlivex chief scientific and medical officer Dr. Dror Mevorach, head of internal medicine and of one of Hadassah’s coronavirus wards. It works by restoring balance to the immune system. Mevorach said Allocetra “may have utility as a safe and efficacious treatment … regardless of the specific coronavirus mutation that afflicted the patients, and across different life-threatening, high mortality clinical indications with high unmet medical needs.” To read the original article click here. For more articles from Israel21c click here.

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Lab Study Reveals Effective Treatment for COVID-19

AHA Publisher — Mon, 18 Jan 2021 08:00:22 +0000

Rush University Medical Center via News-Medical Net – A new potential therapy for COVID-19 developed by researchers at Rush University Medical Center has shown success in preventing the disease’s symptoms in mice. In a study, mouse models with COVID-19 showed positive results when a peptide (chain of amino acids) was introduced nasally. The peptide proved effective in reducing fever, protecting the lungs, improving heart function and reversing cytokine storm -; the immune system overreacting to an infection and flooding the bloodstream with inflammatory proteins. The researchers also report success in preventing the disease from progression in the report of their results published Jan. 11 in the Journal of Neuroimmune Pharmacology. SARS-CoV-2, the virus that causes COVID-19, binds to an enzyme called ACE2 to enter and infect human cells. In response, the research team designed a hexapeptide (a peptide with six amino acids) that inhibits the virus from binding with ACE2. “This could be a new approach to prevent SARS-CoV-2 infection and protect COVID-19 patients from breathing problems and cardiac issues,” said Kalipada Pahan, PhD, the Floyd A. Davis Professor of Neurology at the Rush University Medical Center and a research career scientist at the Jesse Brown VA Medical Center, who led the study. Many patients with COVID-19 in intensive care units suffer from cytokine storm, which affects lungs, heart and other organs. Although anti-inflammatory therapies such as steroids are available to treat the problem, very often these treatments cause suppression of the immune system. The peptide inhibits cytokines that only are produced by the SARS-CoV-2 spike protein, not other inflammatory stimuli, indicating that this peptide would not cause immunosuppression.” (Kalipada Pahan, PhD, Floyd A. Davis Professor of Neurology, Rush University Medical Center) Although vaccines for COVID-19 are becoming available, their distribution nationally and globally will take months and possibly years in some part of the world. In addition, vaccines may not entirely prevent the spread of COVID-19. For example, despite flu vaccination, about 40,000 to 50,000 people die each year in United States from the flu. Therefore, a specific medicine for reducing inflammatory events and treating respiratory and cardiac problems caused by COVID-19 will be necessary for better management of the disease even in the post-vaccine era. “If our peptide results can be replicated in COVID-19 patients, it would be a remarkable advance in controlling this devastating pandemic,” Pahan said. To read the original article click here.

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Novel Way to Protect Your Lungs

AHA Publisher — Fri, 15 Jan 2021 08:00:50 +0000

Al Sears, MD, CNS – The recovery rate from Covid-19 is about 99.75%. Fortunately, most people who have had it won’t have any long-lasting damage. Unfortunately, in about 5% percent of critical cases, the virus triggers an overreaction of the immune system in what is known as a “cytokine storm.” This leads to inflammation that can damage the walls and lining of the air sacs in your lungs. The result is acute respiratory distress syndrome – or ARDS. But there’s a novel way you can protect your lungs. A new study published in the Journal of Cellular and Molecular Medicine found that CBD can reduce – and even reverse – this lung damage by normalizing levels of an inflammation-causing peptide called apelin. Apelin is made by cells in the blood, brain, heart, fat and lung tissue. It plays a major role in regulating your blood pressure, while also keeping inflammation down. When you’re infected with coronavirus, your levels of this peptide plummet. But researchers say that even when levels were close to zero in patients with ARDS, treatment with CBD increased apelin blood levels by 20 times – and restored lung function back to normal levels. The study authors found that using CBD also:1 Relaxed cells lining blood vessels Reduced excessive lung inflammation Increased oxygen levels Repaired damage to the lungs, including scarring and swelling This study backs up an earlier study that found CBD helps open bronchial passes allowing patients with COPD to breathe more easily and avoid low blood oxygen levels.2 Heal Your Lungs With the Right Kind of CBD When it comes to CBD, you want to get the greatest – and fastest – benefit. And that means increasing its bioavailability. Like most medications and supplements, it’s best to take CBD with a meal because it increases the absorption. And the more CBD you absorb in your bloodstream, the more potent the effect. You know CBD can be taken a lot of different ways: in tinctures, capsules, vaping, balms, edibles and more. Each method has benefits, but some allow for more CBD to be directly absorbed than others. For example, eating or swallowing CBD requires digestion, which means some of the CBD gets broken down by your liver before circulating into your bloodstream. Tinctures, on the other hand, get absorbed more quickly into your bloodstream under your tongue. I’ve found that an oral spray that uses nanotechnology is the most bioavailable. That’s because it’s a quicker, more direct route to the bloodstream, and it avoids the liver’s “first pass” effect, which lowers CBD bioavailability. In fact, nanotechnology gets 1,500% more CBD past your cell membranes.3 When you’re having trouble with your lungs, that’s pretty important. To get maximum benefit, spray the liquid under your tongue, hold it without talking for 60 seconds and then swallow. 3 More Ways to Increase Bioavailability Look for an emulsified product. Some products emulsify their CBD using nanotechnology. This breaks CBD down into even smaller molecules. The smaller and more dispersed the molecules are, the more bioavailable they are, because they pass more easily through cell membranes and into the bloodstream than larger CBD particles.4 Take it with healthy fats. CBD is a fat-soluble compound, meaning it dissolves in fats. This breaks CBD down into smaller molecules that are more easily absorbed by the body. One way to increase CBD’s bioavailability is to mix it with a healthy high-fat snack or meal. A recent study found that people who took CBD with high-fat foods increased their absorption up to 14 times more than those who took it on an empty stomach.5 Look for full-spectrum CBD. Terpenes are fatty oils found in the essential oils of almost all plants. They occur naturally in hemp and are extracted along with CBD and other compounds to create full-spectrum CBD products. These compounds work together and amplify each other’s benefits, a synergy known as the “entourage effect.” Terpenes increase CBD bioavailability and enhance the therapeutic effects of cannabinoids. Note: There is one method of taking CBD I don’t recommend and that’s vaping. That’s especially true if you already have lung damage. It’s true that there aren’t a lot of studies. But with so many other safe, effective and fast ways to get your CBD, why take the risk? To Your Good Health, Al Sears, MD, CNS 1. Khodadadi H, et al. “Cannabidiol modulates cytokine storm in acute respiratory distress syndrome induced by simulated viral infection using synthetic RNA.” Cannabis Cannabinoid Res. 2020; 5(3): 197–201. 2. Makwana R, et al. “The effect of phytocannabinoids on airway hyper-responsiveness, airway inflammation, and cough.” J Pharmacol Exp Ther. 2015 Apr;353(1):169-80. 3. Cherniakov I, et al. “Piperine-pro-nanolipospheres as a novel oral delivery system of cannabinoids: Pharmacokinetic evaluation in healthy volunteers in comparison to buccal spray administration.” J Control Release.2017;266:1-7. 4. Bruni N, et al. “Cannabinoid delivery systems for pain and inflammation treatment.” Molecules. 2018;23(10). 5. Birnbaum AK, et al. “Food effect on pharmacokinetics of cannabidiol oral capsules in adult patients with refractory epilepsy.” Epilepsia. 2019;60(8):1586-1592. To read the original article click here. For more articles from Al Sears, MD click here.

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Could Beta-Blockers Be a Potential Treatment for COVID-19?

AHA Publisher — Wed, 09 Dec 2020 08:00:55 +0000

Interview conducted by Emily Henderson, B.Sc. via News-Medical Net – News-Medical spoke to researchers Dr. Nirmal Robinson, Dr. Vincenzo Desiderio, and Dr. Antonio Barbieri about their latest research into beta-blockers, and how they could potentially be used to treat COVID-19. What provoked your research into the current COVID-19 pandemic? We have been working on adrenergic receptors for a few years, in the context of its role in cancer progression and possibly to target them for cancer treatment. Adrenergic receptors are also involved in regulating the immune system and inflammation. When the initial data on inflammation associated with COVID-19 was published, we realized that the processes involved, namely the activation of inflammatory T lymphocytes and cytokines release, were similar to what we have observed when beta2-adrenergic receptors are stimulated in cancer settings. What are the three stages of SARS-CoV-2 infection? The progression of COVIDS-19 has been divided into three main stages: stage I—viral response, stage II—pulmonary phase, and stage III—hyper inflammation phase. Once the patients enter stage III, they will most likely need ventilation and it becomes difficult to manage. Why is it of high importance that we are able to find an effective therapy to slow down or stop the progression of the virus into its third stage? The third stage is the last and most severe stage whereby the patients are affected by acute respiratory distress syndrome (ARDS), requiring ventilation in an intensive care unit. This is the stage in which hyper inflammation due to cytokine storms can induce small blood clots throughout the bloodstream, blocking small blood vessels, causing death. Preventing the progression to this phase could possibly give the needed time for the body to recover as it is not the virus itself that causes the damage, rather the excessive immune response to the virus. Why are patients with high blood pressure, diabetes, and heart disease at a higher risk of developing a severe infection? It is a known fact that people with diabetes are at higher risk of severe complications from infection in general, as increased blood sugar levels can reduce the ability of the immune system to fight infection. On the other hand, an acute infection might raise sugar levels and make it difficult to control. Similarly, about 30% of hospitalized Flu-patients have diabetes, hence diabetes patients are strongly recommended to receive the flu vaccination. COVID-19 associated severe complications are mainly caused by uncontrollable inflammation following a “cytokine storm” which is the release of abundant inflammatory cytokines that affect blood vessels among other structures. Diabetes patients as well as patients with hypertension are characterized by increased cytokine release and hyperinflammatory state. Also, inflammation will affect the blood by making it thicker putting organs such as the heart, kidney, and lungs under stress. One still unconfirmed theory also suggests that people with diabetes and high blood pressure have higher ACE2 receptors, the viral receptors used by SARS-CoV-2 to access the cells and generate infection, making them easier to infect. In your research, you looked at using beta-blockers to potentially treat COVID-19. What are beta-blockers such as propranolol currently used for? Beta-blockers are a class of medications that work by temporarily stopping or reducing the action of the beta-adrenergic receptors, involved in the body’s natural ‘fight-or-flight’ response. In return, they reduce stress on certain parts of the body, such as the heart and blood vessels in the brain. They are prevalently used to manage abnormal heart rhythm, hypertension and to protect the heart from recurring myocardial infarction. Propranolol is a non-selective beta-blocker because it blocks both beta 1 and beta 2 receptors. Propranolol is no longer used to treat heart conditions, but it has been recently repurposed for several pathologies such as cancer, haemangioma, rheumatoid arthritis, and anxiety. How is the spread of cancer in the lung similar in its inflammatory profile to COVID-19? Inflammation and oxidative stress predispose to the development of cancer and promote all stages of tumorigenesis. Cancer cells, as well as surrounding stromal and inflammatory cells, engage with each other to form an inflammatory tumor microenvironment (TME). Clinical studies using non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin have shown that the inhibition of inflammation reduces the incidence and mortality in many cancers. In addition, specific inhibition of cytokines such as interleukin 1β (IL-1β) with canakinumab, significantly reduces the risk of lung cancer development. In our model of melanoma lung metastasis, cytokines produced such as interleukin-6, interleukin-1β, interferon-γ are very similar to COVID-19 infections. What current treatments are being trialed to treat COVID-19? What are some of the limitations of these methods so far? At the moment approximately 360 drugs are in human trials to treat COVID-19, but dexamethasone (a corticosteroid) has been proven to be significantly effective in clinical trials. Anticoagulants (usually low molecular weight heparins) are also used to reduce blood clots in blood vessels. Corticosteroids are broad anti-inflammatory drugs that depress the entire immune system, so while they are able to mitigate inflammation, they also reduce the ability of the immune system to fight the virus. An ideal therapy should target only the dangerous components of immune responses that are responsible for the adverse inflammatory reactions caused by specific cytokines, and spare the ability of the immune system to control the virus. Can you describe how you carried out your research into beta-blockers and their potential effectiveness as a treatment for COVID-19? Our research is based on our investigations into the beta-2 adrenergic pathway in cancer. Beta-2 adrenergic receptor (ADBR2) is highly expressed in many kinds of cancers and contributes to cancer growth and spread (metastasis). We have shown that targeting ADBR2 can reduce cancer growth and metastasis thus can be used as an adjunct therapy with the current therapy and help in overcoming drug resistance. ADBR2 is normally expressed on blood vessels, lungs, and cells of the immune system. We believe that blocking ABDR2 can reduce potentially dangerous immune responses without depressing the entire immune system. Many supporting pieces of evidence show that the major symptoms of COVID-19 infection are associated with over-activation of what is called Th17 response and β2-AR signals have been described to have a central role in promoting Th17 response in disease such as rheumatoid arthritis. Non-selective beta-blockers have been used in clinical settings to reduce inflammation and Th17 response. So, we believe that a similar effect can be obtained in COVID-19 patients. Moreover, beta-adrenergic receptor antagonists have been shown to be effective in dissolving blood clots. For these reasons, we suggest that beta-blockers such as propranolol should be considered for clinical trials to treat COVID-19. What did you discover? We have highlighted the similarity between cancer lung metastases microenvironment and COVID-19 in terms of inflammation and cytokine profile. We have also pointed out that targeting the adrenergic pathway might be an effective way to reduce inflammation and prevent cytokine storms, thus reducing the risk for patients to enter the most severe phase 3 of the disease. We strongly believe that this strategy is worth pursuing in a clinical setting. Can you describe the mechanism behind beta-blockers that help to reduce inflammation and rebalance our immune system? β2-adrenergic receptors are expressed by all the cells of the immune system, including T and B lymphocytes, dendritic cells (DCs), and macrophages. The specific role of adrenergic signaling in regulating immune responses and inflammation is still under debate. However, evidence support that activation of β2-adrenergic receptors leads to the generation of reactive oxygen species (ROS) which trigger the secretion of inflammatory cytokines. Moreover, catecholamines (activators of β2-adrenergic receptors) can promote the development of the inflammatory lymphocytes (specifically the Th17 response) which has been recognized to be responsible for the severe immune reaction associated with COVID -19. In cancer patients, propranolol reduces this inflammatory response, as well as the disease-associated anxiety. Another cytokine IFN- γ can exert direct antiviral effects on infected cells as well as neighboring cells. Interestingly, propranolol does not lower the levels of this anti-viral cytokine. Therefore, we think that beta-blockers could balance the immune system against SARS-CoV2 by reducing the inflammation that is lethal to patients but at the same time preserve the cytokines which are beneficial to kill the virus. Do you believe that your research could potentially help to cure COVID-19? Beta-blockers do not prevent virus replication and spread. On the other hand, the strategy we propose could help in mitigating the cytokine storm induced inflammation in COVID-19 patients thus reducing the lethality. What are the next steps in your research into beta-blockers as a potential treatment for COVID-19? Beta-blockers such as propranolol has been used for decades and are very safe drugs, therefore we believe that it is worthy to conduct a clinical trial on COVID-19 patients at the early stage of the disease to prove its effectiveness. Where can readers find more information? Barbieri A, Robinson N, Palma G, Maurea N, Desiderio V, Botti G. Can Beta-2-Adrenergic Pathway Be a New Target to Combat SARS-CoV-2 Hyperinflammatory Syndrome?-Lessons Learned From Cancer. Front Immunol. 2020 Sep 30;11:588724. doi: 10.3389/fimmu.2020.588724. PMID: 33117402; PMCID: PMC7561388. https://www.frontiersin.org/articles/10.3389/fimmu.2020.588724/full To read the original article click here.

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Cancer Patients May Not Have Higher Covid-19 Risk

AHA Publisher — Mon, 07 Sep 2020 07:00:00 +0000

Brian Blum via Israel21c – Throughout the Covid-19 pandemic, it has been assumed that cancer patients were in the highest at-risk group. An early study from China seemed to confirm this. In addition, thousands of cancer patients in the UK were sent text messages advising them to shelter in place for the indefinite future. But that assumption may be wrong. A study by researchers at the Technion – Israel Institute of Technology and the Rambam Health Care Campus in Haifa suggests that cancer patients not only have no higher risk than the general population, but changes to the immune system as a result of cancer treatments may give them even more protection from the most severe Covid-19 symptoms. Prof. Irit Ben-Aharon, director of the oncology department at Rambam, and Prof. Yuval Shaked, head of the Rapaport Integrated Center for Cancer Research at the Technion, analyzed the blood tests of 164 cancer patients who were in active anti-cancer treatment and 107 healthcare workers between March and June 2020. All underwent blood tests at three different times. The researchers found that the rate for developing Covid-19 antibodies among both groups was around 2%. For cancer patients it was 2.4% and for those in the control group it was 1.94%. “We were surprised to find that cancer patients and healthy subjects developed antibodies at similar rates,” says Ben-Aharon. Even more surprising: No symptomatic corona patients were detected in either group. “Our hypothesis is that the different response of cancer patients to the disease is related to the fact that the anti-cancer treatment changes the profile of the immune system,” Shaked explains. In particular, the researchers speculate that oncological treatments (especially immunotherapy) may prevent “cytokine storms” where a Covid-19 patient’s immune system goes into dangerous overdrive causing lung inflammation. Ben-Aharon and Shakedsurmise that these changes to the immune system also shield cancer patients against heart disease. The news from Haifa has potentially far-reaching implications during the Covid-19 pandemic. Defining cancer patients as an at-risk group led many to avoid hospitals and delay oncological treatments and elective surgeries. According to Shaked and Ben-Aharon, there’s no real basis for such sweeping affiliation of cancer patients to the broad risk group of people with other background diseases. The results were published last week in a special issue of the scientific journal Cancers. The earlier Chinese study, published in March in The Lancet, sampled 1,590 patients with confirmed Covid-19, 18of whom were cancer patients. The Technion/Rambam study was relatively small as well, so even with positive preliminary results, the authors are calling for further research. Dr. Tal Goshen-Lego of the Rambam Oncology Division collaborated on the research. The study was supported by the Israel Cancer Research Foundation and the European Commission. To read the original article click here. For more articles from Israel21c click here.

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Quieting the Storm: Acupuncture Activates Inflammation-Regulating Pathways, Tames Cytokine Storm

AHA Publisher — Mon, 17 Aug 2020 07:00:14 +0000

Harvard Medical School via Newswise – A team of researchers led by neuroscientists at Harvard Medical School has successfully used acupuncture to tame cytokine storm in mice with systemic inflammation. In the study, published Aug. 12 in Neuron, acupuncture activated different signaling pathways that triggered either a pro-inflammatory or an anti-inflammatory response in animals with bacterially induced systemic inflammation. Further, the team found that three factors determined how acupuncture affected response: site, intensity and timing of treatment. Where in the body the stimulation occurred, how strong it was and when the stimulation was administered yielded dramatically different effects on inflammatory markers and survival. The team’s experiments represent a critical step toward defining the neuroanatomical mechanisms underlying acupuncture and offer a roadmap for harnessing the approach for the treatment of inflammatory diseases. The scientists caution, however, that before any therapeutic use, the observations must be confirmed in further research—in animals as well as in humans—and the optimal parameters for acupuncture stimulation must be carefully defined. “Our findings represent an important step in ongoing efforts not only to understand the neuroanatomy of acupuncture but to identify ways to incorporate it into the treatment arsenal of inflammatory diseases, including sepsis,” said study principal investigator Qiufu Ma, professor of neurobiology in the Blavatnik (Institute at Harvard Medical School and a researcher at Dana-Farber Cancer Institute). In the study, acupuncture stimulation influenced how animals coped with cytokine storm—the rapid release of large amounts of cytokines, inflammation-fueling molecules. The phenomenon has gained mainstream attention as a complication of severe COVID-19, but this aberrant immune reaction can occur in the setting of any infection and has been long known to physicians as a hallmark of sepsis, an organ-damaging, often-fatal inflammatory response to infection. Sepsis is estimated to affect 1.7 million people in the United States and 30 million people worldwide each year. Acupuncture, rooted in traditional Chinese medicine, has recently grown more integrated into Western medicine, particularly for the treatment of chronic pain and gastrointestinal disorders. The approach involves mechanical stimulation of certain points on the body’s surface—known as acupoints. The stimulation purportedly triggers nerve signaling and remotely affects the function of internal organs corresponding to specific acupoints. Yet, the basic mechanisms underlying acupuncture’s action and effect have not been fully elucidated. The new study is an important step in mapping the neuroanatomy of acupuncture, the research team said. As a neurobiologist who studies the fundamental mechanisms of pain, Ma has been curious about the biology of acupuncture for years. He was intrigued by a 2014 paper which showed that using acupuncture in mice could alleviate systemic inflammation by stimulating the vagal-adrenal axis—a signaling pathway in which the vagus nerve carries signals to the adrenal glands—to trigger the glands to release dopamine. Ma’s curiosity was further intensified by work published in 2016 showing that vagus-nerve stimulation tamed the activity of inflammatory molecules and lessened symptoms of rheumatoid arthritis. In the current study, researchers used electroacupuncture—a modern version of the traditional manual approach that involves the insertion of ultra-thin needles just under the skin in various areas of the body. Instead of needles, electroacupuncture uses very thin electrodes inserted into the skin and into the connective tissue, offering better control of stimulation intensities. Building on previous research pointing to neurotransmitters’ role in inflammation regulation, the researchers focused on two specific cell types known to secrete them—chromaffin cells that reside in the adrenal glands and noradrenergic neurons that are located in the peripheral nerve system and directly connected to the spleen through an abundance of nerve fibers. Chromaffin cells are the body’s main producers of the stress hormones adrenaline and noradrenaline and of dopamine, while noradrenergic neurons release noradrenaline. In addition to their well-established functions, adrenaline, noradrenaline and dopamine, the researchers said, appear to play a role in inflammation response—an observation that’s been borne out in previous research and is now reaffirmed in the experiments of the current study. The team wanted to determine the precise role these nerve cells play in the inflammatory response. To do so, they used a novel genetic tool to ablate chromaffin cells or noradrenergic neurons. This allowed them to compare the response to inflammation in mice with and without these cells to determine just whether and how they were involved in modulating inflammation. The markedly different response in mice with and without such cells conclusively pinpointed these nerve cells as key regulators of inflammation. In one set of experiments, researchers applied low-intensity electroacupuncture (0.5 milliamperes) to a specific point on the hind legs of mice with cytokine storm caused by a bacterial toxin. This stimulation activated the vagus-adrenal axis, inducing secretion of dopamine from the chromaffin cells of the adrenal glands. Animals treated this way had lower levels of three key types of inflammation-inducing cytokines and had greater survival than control mice—60 percent of acupuncture-treated animals survived, compared with 20 percent of untreated animals. Intriguingly, the researchers observed, the vagus-adrenal axis could be activated through hindlimb electroacupuncture but not from abdominal acupoints—a finding that shows the importance of acupoint selectivity in driving specific anti-inflammatory pathways. In another experiment, the team delivered high-intensity electroacupuncture (3 milliamperes) to the same hindleg acupoint as well as to an acupoint on the abdomen of mice with sepsis. That stimulation activated noradrenergic nerve fibers in the spleen. The timing of treatment was critical, the researchers observed. High-intensity stimulation of the abdomen produced markedly different outcomes depending on when treatment occurred. Animals treated with acupuncture immediately before they developed cytokine storm, experienced lower levels of inflammation during subsequent disease and fared better. This preventive measure of high-intensity stimulation increased survival from 20 to 80 percent. By contrast, animals that received acupuncture after disease onset and during the peak of cytokine storm experienced worse inflammation and more severe disease. The findings demonstrate how the same stimulus could produce dramatically different results depending on location, timing and intensity. “This observation underscores the idea that if practiced inappropriately, acupuncture could have detrimental results, which I don’t think is something people necessarily appreciate,” Ma said. If borne out in further work, Ma added, the findings suggest the possibility that electroacupuncture could one day be used as a versatile treatment modality—from adjunct therapy for sepsis in the intensive care unit to more targeted treatment of site-specific inflammation, such as in inflammatory diseases of the gastrointestinal tract. Another possible use, Ma said, would be to help modulate inflammation resulting from cancer immune therapy, which while lifesaving can sometimes trigger cytokine storm due to overstimulation of the immune system. Acupuncture is already used as part of integrative cancer treatment to help patients cope with side effects of chemotherapy and other cancer treatments. To read the original article click here.

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